Inhibitors of severe acute respiratory syndrome (SARS) 3C-like proteinase

ABSTRACT

The invention relates to methods of inhibiting SARS-related coronavirus viral replication activity comprising contacting a SARS-related coronavirus protease with a therapeutically effective amount of a rhinovirus protease inhibitor, and compositions comprising the same.

BACKGROUND OF THE INVENTION

[0001] The invention relates to methods of inhibiting Severe AcuteRespiratory Syndrome (SARS) viral replication activity comprisingcontacting a SARS-related coronavirus 3C-like proteinase with atherapeutically effective amount of a rhinovirus 3C protease inhibitor.The invention further relates to pharmaceutical compositions containingthe rhinovirus 3C proteinase (RVP) inhibitor in a mammal byadministering effective amounts of such rhinovirus 3C proteinaseinhibitor.

[0002] A worldwide outbreak of Severe Acute Respiratory Syndrome-relatedvirus(es) (SARS) has been associated with exposures originating from asingle ill health care worker from Guangdong Province, China. Recently,the causative agent has been identified as a novel coronavirus. There isa need in the art for an effective treatment for the SARS-relatedcoronavirus.

[0003] In particular, recent evidence strongly implicates a newcoronavirus as the causative agent of SARS (CDC). Coronavirusreplication and transcription function is encoded by the so-called“replicase” gene (Thiel, Herold et al. 2001), which consists of twooverlapping polyproteins that are extensively processed by viralproteases. The C-proximal region is processed at eleven conservedinterdomain junctions by the coronavirus main or “3C-like” protease(Ziebuhr, Snijder et al. 2000). The name “3C-like” protease derives fromcertain similarities between the coronavirus enzyme and the well-knownpicornavirus 3C proteases (Gorbalenya, Koonin et al. 1989). Theseinclude substrate preferences, use of cysteine as an active sitenucleophile in catalysis, and similarities in their putative overallpolypeptide folds. Very recently Hilgenfeld and colleagues published ahigh-resolution X-ray structure of the porcine transmissiblegastroenteritis coronavirus main protease (Anand, Palm et al. 2002).Atomic coordinates are available through the Protein Data Bank underaccession code 1LVO.

[0004] For almost 10 years, research organizations like Pfizer-La Jollahave been engaged in an effort to discover and develop drugs withutility for treating the common cold by targeting a key enzyme inrhinovirus replication, namely the 3C protease (Matthews, Smith et al.1994). The picornaviruses are a family of tiny non-envelopedpositive-stranded RNA-containing viruses that infect humans and otheranimals. These viruses include the human rhinoviruses, humanpolioviruses, human coxsackieviruses, human echoviruses, human andbovine enteroviruses, encephalomyocarditis viruses, meningitis virus,foot and mouth viruses, hepatitis A virus, and others. Picomaviralinfections may be treated by inhibiting the proteolytic 3C enzymes.These enzymes are required for the natural maturation of thepicornaviruses. They are responsible for the autocatalytic cleavage ofthe genomic, large polyprotein into the essential viral proteins.Members of the 3C protease family are cysteine proteases, where thesulfhydryl group most often cleaves the glutamine-glycine amide bond.Inhibition of 3C proteases is believed to block proteolytic cleavage ofthe polyprotein, which in tum can retard the maturation and replicationof the viruses by interfering with viral particle production.

[0005] Potent, non-toxic agents with broad-spectrum activity againstmultiple rhinovirus serotypes have been identified (Patick, Binford etal. 1999). Significant catalytic and structural similarities betweenrhinovirus 3C protease and coronavirus “3C-like” main protease suggestthat selected inhibitors of rhinovirus 3C protease are useful againstcoronavirus main protease.

SUMMARY OF THE INVENTION

[0006] The present invention provides methods of inhibiting the activityof a coronavirus 3C protease (also known as proteinase), comprisingcontacting the coronavirus 3C protease with an effective amount of apicornavirus inhibitor compound, and preferably a rhinovirus inhibitorcompound or agent.

[0007] The present invention provides a novel method of interfering withor preventing SARS viral replication activity comprising contacting aSARS protease with a therapeutically effective amount of a rhinovirusprotease inhibitor.

[0008] In one embodiment of the present invention, the SARS coronavirus3C-like protease inhibitor is administered orally or intravenously.

[0009] The present invention also provides a method of treating acondition that is mediated by coronavirus 3C-like protease activity in apatient by administering to said patient a pharmaceutically effectiveamount of a rhinovirus protease inhibitor.

[0010] The present invention also provides a method of targeting SARSinhibition as a means of treating indications caused by SARS-relatedviral infections.

[0011] The present invention also provides a method of targeting viralor cellular targets identified by using rhinovirus inhibitors againstSARS coronavirus 3C-like protease for treating indications caused bySARS-related viral infections.

[0012] The present invention also provides a method of identifyingcellular or viral pathways interfering with the functioning of themembers of which could be used for treating indications caused by SARSinfections by administering a rhinovirus protease inhibitor.

[0013] The present invention also provides a method of using rhinovirusprotease inhibitors as tools for understanding mechanism of action ofother SARS inhibitors.

[0014] The present invention also provides a method of using rhinovirusprotease inhibitors for carrying out gene profiling experiments formonitoring the up or down regulation of genes for the purposed ofidentifying inhibitors for treating indications caused by SARSinfections.

[0015] The present invention further provides a pharmaceuticalcomposition for the treatment of SARS in a mammal containing an amountof a rhinovirus protease inhibitor that is effective in treating SARSand a pharmaceutically acceptable carrier.

[0016] In another aspect, the invention provides a method of interferingwith or preventing SARS related coronavirus viral replication activitycomprising contacting a SARS related coronavirus protease with atherapeutically effective amount of a rhinovirus 3C protease inhibitorof formula I:

[0017] wherein

[0018] M is O or S;

[0019] R₁ is H, F, an alkyl group, OH, SH, or an O-alkyl group;

[0020] R₂ and R₅ are independently selected from H,

[0021] or an alkyl group, wherein said alkyl group is different from

[0022] with the proviso that at least one of R₂ or R₅ must be

[0023] and wherein, when R₂ or R₅ is

[0024] X is ═CH or ═CF and Y₁ is ═CH or ═CF,

[0025] or X and Y₁ together with Q′ form a three-membered ring in whichQ′ is —C(R₁₀)(R₁₁)— or —O—, X is —CH— or —CF—, and Y₁ is —CH—, —CF—, or—C(alkyl)—, where R₁₀ and R₁₁ independently are H, a halogen, or analkyl group, or, together with the carbon atom to which they areattached, form a cycloalkyl group or a heterocycloalkyl group,

[0026] or X is —CH₂—, —CF₂—, —CHF—, or —S—, and Y₁ is —O—, —S—, —NR₁₂—,—C(R₁₃)(R₁₄)—, —C(O)—, —C(S)—, or —C(CR₁₃R₁₄)—,

[0027] wherein R₁₂ is H or alkyl, and R₁₃ and R₁₄ independently are H,F, or an alkyl group, or, together with the atoms to which they arebonded, form a cycloalkyl group or a heterocycloalkyl group;

[0028] A₁ is C, CH, CF, S, P, Se, N, NR₁₅, S(O), Se(O), P—OR₁₅, orP—NR₁₅R₁₆, wherein R₁₅ and R₁₆ independently are an alkyl group, acycloalkyl group, a heterocycloalkyl group, an aryl group, or aheteroaryl group, or, together with the atom to which they are bonded,form a heterocycloalkyl group;

[0029] D₁ is a moiety with a lone pair of electrons capable of forming ahydrogen bond; and

[0030] B₁ is H, F, an alkyl group, a cycloalkyl group, aheterocycloalkyl group, an aryl group, a heteroaryl group, —OR₁₇, —SR₁₇,—NR₁₇R₁₈, —NR₁₉NR₁₇R₁₈, or —NR₁₇OR₁₈,

[0031] wherein R₁₇, R₁₈, and R₁₉ independently are H, an alkyl group, acycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroarylgroup, or an acyl group;

[0032] and with the provisos that when D₁ is the moiety □N with a lonepair of electrons capable of forming a hydrogen bond, B₁ does not exist;and when A₁ is an sp³ carbon, B₁ is not —NR₁₇R₁₈ when D₁ is the moiety—NR₂₅R₂₆ with a lone pair of electrons capable of forming a hydrogenbond, wherein R₂₅ and R₂₆ are independently H, an alkyl group, acycloalkyl group, a heterocycloalkyl group, an aryl group, or aheteroaryl group;

[0033] and wherein D₁-A₁-B₁ optionally forms a nitro group where A₁ isN;

[0034] and further wherein, when R₂ or R₅ is

[0035] X is ═CH or ═CF and Y₂ is ═C, ═CH, or ═CF,

[0036] or X and Y₂ together with Q′ form a three-membered ring in whichQ′ is —C(R₁₀)(R₁₁)— or —O—, X is —CH— or —CF—, and Y₂ is —CH—, —CF—, or—C(alkyl)—, where R₁₀ and R₁₁ independently are H, a halogen, or analkyl group, or, together with the carbon atom to which they areattached, form a cycloalkyl group or a heterocycloalkyl group,

[0037] or X is —CH₂—, —CF₂—, —CHF—, or —S—, and Y₂ is —O—, —S—,—N(R′₁₂)—, —C(O)—, —C(R′₁₃)(R′₁₄)—, —C(S)—, or —C(CR′₁₃R′₁₄)—,

[0038] wherein R′₁₂ is H, an alkyl group, a cycloalkyl group, aheterocycloalkyl group, an aryl group, a heteroaryl group, —OR′₁₃,—NR′₁₃R′₁₄, —C(O)—R′₁₃, —SO₂R′₁₃, or —C(S)R′₁₃, and R′₁₃ and R′₁₄,independently are H, F, or an alkyl group, a cycloalkyl group, aheterocycloalkyl group, an aryl group, or a heteroaryl group, or,together with the atom to which they are attached, form a cycloalkylgroup or a heterocycloalkyl group;

[0039] A₂ is C, CH, CF, S, P, Se, N, NR₁₅, S(O), Se(O), P—OR₁₅, orP—NR₁₅R₁₆, wherein R₁₅ and R₁₆ independently are an alkyl group, acycloalkyl group, a heterocycloalkyl group, an aryl group, or aheteroaryl group, or, together with the atom to which they are bonded,form a heterocycloalkyl group;

[0040] D₂ is a moiety with a lone pair of electrons capable of forming ahydrogen bond; and

[0041] B₂ is H, F, an alkyl group, a cycloalkyl group, aheterocycloalkyl group, an aryl group, a heteroaryl group, —OR₁₇, —SR₁₇,—NR₁₇R₁₈, —NR₁₉NR₁₇R₁₈, or —NR₁₇OR₁₈,

[0042] wherein R₁₇, R₁₈, and R₁₉ independently are H, an alkyl group, acycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroarylgroup, or an acyl group;

[0043] and further wherein any combination of Y₂, A₂, B₂, and D₂optionally can form a cycloalkyl group, a heterocycloalkyl group, anaryl group, or a heteroaryl group;

[0044] R₃ and R₆ are independently H, F, an alkyl group, a cycloalkylgroup, a heterocycloalkyl group, an aryl group, a heteroaryl group,—C(O)R₁₇, —OR₁₇, —SR₁₇, —NR₁₇R₁₈, —NR₁₉NR₁₇R₁₈, or —NR₁₇OR₁₈,

[0045] wherein R₁₇, R₁₈, and R₁₉ independently are H, an alkyl group, acycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroarylgroup, or an acyl group;

[0046] or, R₃ and R₆, together with the carbon atom to which they areattached, form a cycloalkyl group or a heterocycloalkyl group;

[0047] R₇ is H, an alkyl group, a cycloalkyl group, a heterocycloalkylgroup, an aryl group, a heteroaryl group, —OR₁₇, —SR₁₇, —NR₁₇R₁₈,—NR₁₉NR₁₇R₁₈, or —NR₁₇OR₁₈,

[0048] wherein R₁₇, R₁₈, and R₁₉ independently are H, an alkyl group, acycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroarylgroup, or an acyl group;

[0049] or R₇, together with R₃ or R₆ and the atoms to which they areattached, forms a heterocycloalkyl group;

[0050] R₂₀ is H, OH, or any suitable organic moiety; and

[0051] Z and Z₁ are independently H, F, an alkyl group, a cycloalkylgroup, a heterocycloalkyl group, an aryl group, a heteroaryl group,—C(O)R₂₁, —CO₂R₂₁, —CN, —C(O)NR₂₁R₂₂, —C(O)NR₂₁OR₂₂, —C(S)R₂₁,—C(S)NR₂₁R₂₂, —NO₂₁, —SOR₂₁, —SO₂R₂₁, —SO₂NR₂₁R₂₂, —SO(NR₂₁)(OR₂₂),—SONR₂₁, —SO₃R₂₁, —PO(OR₂₁)₂, —PO(R₂₁)(R₂₂), —PO(NR₂₁R₂₂)(OR₂₃),PO(NR₂₁R₂₂)(NR₂₃R₂₄), —C(O)NR₂₁NR₂₂R₂₃, or —C(S)NR₂₁NR₂₂R₂₃,

[0052] wherein R₂₁, R₂₂, R₂₃, and R₂₄ are independently H, an alkylgroup, a cycloalkyl group, a heterocycloalkyl group, an aryl group, aheteroaryl group, an acyl group, or a thioacyl group, or wherein any twoof R₂₁, R₂₂, R₂₃, and R₂₄, together with the atom(s) to which they arebonded, form a heterocycloalkyl group;

[0053] or Z₁, as defined above, together with R₁, as defined above, andthe atoms to which Z₁ and R₁ are bonded, form a cycloalkyl orheterocycloalkyl group,

[0054] or Z and Z₁, both as defined above, together with the atoms towhich they are bonded, form a cycloalkyl or heterocycloalkyl group;

[0055] or a pharmaceutically acceptable prodrug, salt, activemetabolite, or solvate thereof; and wherein said compound, orpharmaceutically acceptable prodrug, salt, active metabolite, or solvatethereof, has antipicornaviral activity with an EC₅₀ less than or equalto 10 μM in a HI-HeLa cell culture assay.

[0056] In another aspect, the invention provides a method of interferingwith or preventing SARS related coronavirus viral replication activitycomprising contacting a SARS related coronavirus protease with atherapeutically effective amount of a rhinovirus 3C protease inhibitorof formula II:

[0057] wherein R₁ is:

[0058] or a pharmaceutically acceptable salt, solvate, prodrug, orpharmaceutically active metabolite thereof.

[0059] In still another aspect, the invention provides a method ofinterfering with or preventing SARS related coronavirus viralreplication activity comprising contacting a SARS related coronavirusprotease with a therapeutically effective amount of a rhinovirus 3Cprotease inhibitor of formula IIA:

[0060] or a pharmaceutically acceptable salt, solvate, prodrug, orpharmaceutically active metabolite thereof.

[0061] In yet another aspect, the invention provides a method ofinterfering with or preventing SARS related coronavirus viralreplication activity comprising contacting a SARS related coronavirusprotease with a therapeutically effective amount of a rhinovirus 3Cprotease inhibitor of formula IIB:

[0062] wherein:

[0063] R₁₀ is H or CH₃;

[0064] R₂₀ is H, OH, CH₂OH, or OCH₂Ph;

[0065] R₃₀ is H, OH, or OCH₂Ph;

[0066] R₄₀ is H or CN; and

[0067] R₅₀ is CH₂CH₃, CH₃, CH₂Ph, CH₂CH₂Ph, CH₂CH₂OH, or CH₂(2-pyridyl);

[0068] or a pharmaceutically acceptable salt, solvate, prodrug, orpharmaceutically active metabolite thereof.

[0069] In another aspect, the invention provides a method of interferingwith or preventing SARS related coronavirus viral replication activitycomprising contacting a SARS related coronavirus protease with atherapeutically effective amount of a rhinovirus 3C protease inhibitorof formula IIC:

[0070] wherein R₁₀₀ is CH₃, phenyl, Ph(4-NCH₃), Ph(4-OCH₃), 2-pyridyl,or 2-furyl;

[0071] or a pharmaceutically acceptable salt, solvate, prodrug, orpharmaceutically active metabolite thereof. In another aspect, theinvention provides a method of interfering with or preventing SARSrelated coronavirus viral replication activity comprising contacting aSARS related coronavirus protease with a therapeutically effectiveamount of a rhinovirus 3C protease inhibitor of formula

[0072] In another aspect, the invention provides a method of interferingwith or preventing SARS related coronavirus viral replication activitycomprising contacting a SARS related coronavirus protease with atherapeutically effective amount of a rhinovirus 3C protease inhibitorof formula III:

[0073] wherein:

[0074] R^(a1) is a cycloalkyl, heterocycloalkyl, aryl or heteroarylgroup, provided that R^(a1) is not a substituted pyrrolidinyl, where thecycloalkyl, heterocycloalkyl, aryl or heteroaryl group is unsubstitutedor substituted with one or more suitable substituents;

[0075] R^(c) is a substituent having the formula:

[0076] wherein:

[0077] R^(f) and R^(g) are each independently H or lower alkyl;

[0078] m is 0 or 1;

[0079] p is an integer of from 0 to 5;

[0080] A₁ is CH or N;

[0081] when p is 1, 2, 3, 4, or 5, A₂ is C(R^(h))(R^(i)), N(R^(j)), S,S(O), S(O)₂, or O, and when p is 0, A₂ is C(R^(h))(R^(i))(R^(j)),N(R^(i))(R^(j)), S(R^(i)), S(O)(R^(i)), S(O)₂(R^(i)), or O(R^(i)), whereeach R^(h), R^(i) and R^(j) is independently H or a lower alkyl group;

[0082] each A₃ present is independently C(R^(h))(R^(i)), N(R^(j)), S,S(O), S(O)₂, or O; where each R^(h), R^(i) and R^(j) is independently Hor lower alkyl;

[0083] when p is 1, 2, 3, 4, or 5, A₄ is N(R^(k)), C(R^(h))(R^(i)), orO; and when p is 0, A₄ is N(R^(k))(R^(i)), C(R^(h))(R^(i))(R^(j)), andO(R^(i)), where each R^(h), R^(i) and R^(j) is independently H or loweralkyl, each R^(k) is H, alkyl, aryl, or acyl, and each R^(l) is H,alkyl, or aryl;

[0084] provided that no more than two heteroatoms occur consecutively inthe above-depicted ring formed by A₁, (A₂)_(m), (A₃)_(p), A₄, and C═O,where each dotted line in the ring depicts a single bond when A₂ ispresent and a hydrogen atom when A₂ is absent;

[0085] R^(d) is H, halogen, hydroxyl or an alkyl, alkoxy or alkylthiogroup, where the alkyl, alkoxy or alkylthio group is unsubstituted orsubstituted with one or more suitable substituents;

[0086] R^(b) is H or an alkyl group, unsubstituted or substituted withone or more suitable substituents;

[0087] Z and Z¹ are each independently H, F, an alkyl, cycloalkyl,heterocycloalkyl, aryl or heteroaryl group, where the alkyl, cycloalkyl,heterocycloalkyl, aryl or heteroaryl group is unsubstituted orsubstituted with one or more suitable substituents, —C(O)R^(n) —CO₂R^(n)—CN, —C(O)NR^(n)R^(o), —C(O)NR^(n)OR^(o), —C(S)R^(n), —C(S)OR^(n)—C(S)NR^(n)R^(o), —C(═NR^(n))R^(o), —C(═NR^(n))OR^(o), —NO₂, —SOR^(o),—SO₂R^(n), —SO₂NR^(n)R^(o), —SO₂(NR^(n))(OR^(o)), —SONR^(n), —SO₃R^(n),—PO(OR^(n))₂, —PO(OR^(n))(OR^(o)), —PO(NR^(n)R^(o))(OR^(p)),—PO(NR^(n)R^(o))(NR^(p)R^(q)), —C(O)NR^(n)NR^(o)R^(p),—C(S)NR^(n)NR^(o)R^(p), where R^(n), R^(o), R^(p) and R^(q) are eachindependently H or an alkyl, cycloalkyl, aryl, heterocycloalkyl, acyl orthioacyl group, where the alkyl, cycloalkyl, aryl, heterocycloalkyl,acyl or thioacyl group is unsubstituted or substituted with one or moresuitable substituents, or where any two of the R^(n), R^(o), R^(p) andR^(q), taken together with the atoms to which they are bonded, form aheterocycloalkyl group, which may be optionally substituted,

[0088] or Z and R^(d), together with the atoms to which they are bonded,form a cycloalkyl or heterocycloalkyl group, where Z and R^(d) are asdefined above except for moieties that cannot form the cycloalkyl orheterocycloalkyl group,

[0089] or Z and Z¹, together with the atoms to which they are bonded,form a cycloalkyl or heterocycloalkyl group, where Z and Z¹ are asdefined above (except for moieties that cannot form the cycloalkyl orheterocycloalkyl group);

[0090] or a prodrug, pharmaceutically acceptable salt, pharmaceuticallyactive metabolite, or pharmaceutically acceptable solvate thereof.

[0091] In another aspect, the invention provides a method of interferingwith or preventing SARS related coronavirus viral replication activitycomprising contacting a SARS related coronavirus protease with atherapeutically effective amount of a rhinovirus 3C protease inhibitorof formula IIIA:

[0092] wherein:

[0093] R^(a2) is an alkyl, aryl or heteroaryl group, where the alkyl,aryl or heteroaryl group is unsubstituted or substituted with one ormore suitable substituents; and

[0094] R^(c) is a substituent having the formula:

[0095] wherein:

[0096] R^(f) and R^(g) are each independently H or lower alkyl;

[0097] m is 0 or 1;

[0098] p is an integer of from 0 to 5;

[0099] A₁ is CH or N;

[0100] when p is 1, 2, 3, 4, or 5, A₂ is C(R^(h))(R^(i)), N(R^(j)), S,S(O), S(O)₂, or O, and when p is 0, A₂ is C(R^(h))(R^(i))(R^(j)),N(R^(i))(R^(j)), S(R^(i)), S(O)(R^(i)), S(O)₂(R^(i)), or O(R^(i)), whereeach R^(h), R^(i) and R^(j) is independently H or a lower alkyl group;

[0101] each A₃ present is independently C(R^(h))(R^(i)), N(R^(j)), S,S(O), S(O)₂, or O; where each R^(h), R^(i) and R^(j) is independently Hor lower alkyl;

[0102] when p is 1, 2, 3, 4, or 5, A₄ is N(R^(k)), C(R^(h))(R^(i)), orO; and when p is 0, A₄ is N(R^(k))(R^(i)), C(R^(h))(R^(i))(R^(j)), andO(R^(i)), where each R^(h), R^(i) and R^(j) is independently H or loweralkyl, each R^(k) is H, alkyl, aryl, or acyl, and each R^(l) is H,alkyl, or aryl;

[0103] provided that no more than two heteroatoms occur consecutively inthe above-depicted ring formed by A₁, (A₂)_(m), (A₃)_(p), A₄, and C═O,where each dotted line in the ring depicts a single bond when A₂ ispresent and a hydrogen atom when A₂ is absent;

[0104] R^(d) is H, halogen, hydroxyl or an alkyl, alkoxy or alkylthiogroup, where the alkyl, alkoxy or alkylthio group is unsubstituted orsubstituted with one or more suitable substituents;

[0105] R^(b) is H or an alkyl group, unsubstituted or substituted withone or more suitable substituents;

[0106] Z and Z¹ are each independently H, F, an alkyl, cycloalkyl,heterocycloalkyl, aryl or heteroaryl group, where the alkyl, cycloalkyl,heterocycloalkyl, aryl or heteroaryl group is unsubstituted orsubstituted with one or more suitable substituents, —C(O)R^(n) —CO₂R^(n)—CN, —C(O)NR^(n)R^(o), C(O)NR^(n)OR^(o), —C(S)R^(n), —C(S)OR^(n)—C(S)NR^(n)R^(o), —C(═NR^(n))R^(o), —C(═NR^(n))OR^(o), —NO₂, —SOR^(o),—SO₂R^(n), —SO₂NR^(n)R^(o), —SO₂(NR^(n))(OR^(o)), —SONR^(n), —SO₃R^(n),—PO(OR^(n))₂, —PO(OR^(n))(OR^(o)), —PO(NR^(n)R^(o))(OR^(p)),—PO(NR^(n)R^(o))(NR^(p)R^(q)), —C(O)NR^(n)NR^(o)R^(p),—C(S)NR^(n)NR^(o)R^(p), where R^(n), R^(o), R^(p) and R^(q) are eachindependently H or an alkyl, cycloalkyl, aryl, heterocycloalkyl, acyl orthioacyl group, where the alkyl, cycloalkyl, aryl, heterocycloalkyl,acyl or thioacyl group is unsubstituted or substituted with one or moresuitable substituents, or where any two of the R^(n), R^(o), R^(p) andR^(q), taken together with the atoms to which they are bonded, form aheterocycloalkyl group, which may be optionally substituted,

[0107] or Z and R^(d), together with the atoms to which they are bonded,form a cycloalkyl or heterocycloalkyl group, where Z and R^(d) are asdefined above except for moieties that cannot form the cycloalkyl orheterocycloalkyl group,

[0108] or Z and Z¹, together with the atoms to which they are bonded,form a cycloalkyl or heterocycloalkyl group, where Z and Z¹ are asdefined above (except for moieties that cannot form the cycloalkyl orheterocycloalkyl group);

[0109] or a prodrug, pharmaceutically acceptable salt, pharmaceuticallyactive metabolite, or pharmaceutically acceptable solvate thereof.

[0110] In still another aspect, the invention provides a method ofinterfering with or preventing SARS related coronavirus viralreplication activity comprising contacting a SARS related coronavirusprotease with a therapeutically effective amount of a rhinovirus 3Cprotease inhibitor of formula IIIB:

[0111] wherein:

[0112] R^(a3) is an aryl, heterocycloalkyl, heteroaryl orarylaminocarbonyl group, where the aryl, heterocycloalkyl, heteroaryl orarylaminocarbonyl group is unsubstituted or substituted with one or moresuitable substituents; and

[0113] R^(c) is a substituent having the formula:

[0114] wherein:

[0115] R^(f) and R^(g) are each independently H or lower alkyl;

[0116] m is 0 or 1;

[0117] p is an integer of from 0 to 5;

[0118] A₁ is CH or N;

[0119] when p is 1, 2, 3, 4, or 5, A₂ is C(R^(h))(R^(i)), N(R^(j)), S,S(O), S(O)₂, or O, and when p is 0, A₂ is C(R^(h))(R^(i))(R^(j)),N(R^(i))(R^(j)), S(R^(i)), S(O)(R^(i)), S(O)₂(R^(i)), or O(R^(i)), whereeach R^(h), R^(i) and R^(j) is independently H or a lower alkyl group;

[0120] each A₃ present is independently C(R^(h))(R^(i)), N(R^(j)), S,S(O), S(O)₂, or O; where each R^(h), R^(i) and R^(j) is independently Hor lower alkyl;

[0121] when p is 1, 2, 3, 4, or 5, A₄ is N(R^(k)), C(R^(h))(R^(i)), orO; and when p is 0, A₄ is N(R^(k))(R^(i)), C(R^(h))(R^(i))(R^(j)), andO(R^(l)), where each R^(h), R^(i) and R^(j) is independently H or loweralkyl, each R^(k) is H, alkyl, aryl, or acyl, and each R^(l) is H,alkyl, or aryl;

[0122] provided that no more than two heteroatoms occur consecutively inthe above-depicted ring formed by A₁, (A₂)_(m), (A₃)_(p), A₄, and C═O,where each dotted line in the ring depicts a single bond when A₂ ispresent and a hydrogen atom when A₂ is absent;

[0123] R^(d) is H, halogen, hydroxyl or an alkyl, alkoxy or alkylthiogroup, where the alkyl, alkoxy or alkylthio group is unsubstituted orsubstituted with one or more suitable substituents;

[0124] R^(b) is H or an alkyl group, unsubstituted or substituted withone or more suitable substituents;

[0125] R^(e) is H, halogen, hydroxyl or an alkyl, alkoxy or alkylthiogroup, where the alkyl, alkoxy or alkylthio group is unsubstituted orsubstituted with one or more suitable substituents;

[0126] Z and Z¹ are each independently H, F, an alkyl, cycloalkyl,heterocycloalkyl, aryl or heteroaryl group, where the alkyl, cycloalkyl,heterocycloalkyl, aryl or heteroaryl group is unsubstituted orsubstituted with one or more suitable substituents, —C(O)R^(n) —CO₂R^(n)—CN, —C(O)NR^(n)R^(o), —C(O)NR^(n)OR^(o), —C(S)R^(n), —C(S)OR^(n)—C(S)NR^(n)R^(o), —C(═NR^(n))R^(o), —C(═NR^(n))OR^(o), —NO₂, —SOR^(o),—SO₂R^(n), —SO₂NR^(n)R^(o), —SO₂(NR^(n))(OR^(o)), —SONR^(n), —SO₃R^(n),—PO(OR^(n))₂, —PO(OR^(n))(OR^(o)), —PO(NR^(n)R^(o))(OR^(p)).—PO(NR^(n)R^(o))(NR^(p)R^(q)), —C(O)NR^(n)NR^(o)R^(p),—C(S)NR^(n)NR^(o)R^(p), where R^(n), R^(o), R^(p) and R^(q) are eachindependently H or an alkyl, cycloalkyl, aryl, heterocycloalkyl, acyl orthioacyl group, where the alkyl, cycloalkyl, aryl, heterocycloalkyl,acyl or thioacyl group is unsubstituted or substituted with one or moresuitable substituents, or where any two of the R^(n), R^(o), R^(p) andR^(q) taken together with the atoms to which they are bonded, form aheterocycloalkyl group, which may be optionally substituted,

[0127] or Z and R^(d), together with the atoms to which they are bonded,form a cycloalkyl or heterocycloalkyl group, where Z and R^(d) are asdefined above except for moieties that cannot form the cycloalkyl orheterocycloalkyl group,

[0128] or Z and Z¹, together with the atoms to which they are bonded,form a cycloalkyl or heterocycloalkyl group, where Z and Z¹ are asdefined above (except for moieties that cannot form the cycloalkyl orheterocycloalkyl group);

[0129] or a prodrug, pharmaceutically acceptable salt, pharmaceuticallyactive metabolite, or pharmaceutically acceptable solvate thereof.

[0130] In another aspect, the invention provides a method of interferingwith or preventing SARS related coronavirus viral replication activitycomprising contacting a SARS related coronavirus protease with atherapeutically effective amount of a rhinovirus 3C protease inhibitorof formula IIIC:

[0131] wherein:

[0132] R^(a4) is an aryloxy, heteroaryloxy, alkyloxy, cycloalkyloxy,heterocycloalkyloxy, aryl, cycloalkyl, or heteroaryl group, where thearyloxy, heteroaryloxy, alkyloxy, cycloalkyloxy, heterocycloalkyloxy,aryl, cycloalkyl, or heteroaryl group is unsubstituted or substitutedwith one or more suitable substituents; and

[0133] R^(c) is a substituent having the formula:

[0134] wherein:

[0135] R^(f) and R^(g) are each independently H or lower alkyl;

[0136] m is 0 or 1;

[0137] p is an integer of from 0 to 5;

[0138] A₁ is CH or N;

[0139] when p is 1, 2, 3, 4, or 5, A₂ is C(R^(h))(R^(i)), N(R^(j)), S,S(O), S(O)₂, or O, and when p is 0, A₂ is C(R^(h))(R^(i))(R^(j)),N(R^(i))(R^(j)), S(R^(i)), S(O)(R^(i)), S(O)₂(R^(i)), or O(R^(i)), whereeach R^(h), R^(i) and R^(j) is independently H or a lower alkyl group;

[0140] each A₃ present is independently C(R^(h))(R^(i)), N(R^(j)), S,S(O), S(O)₂, or O; where each R^(h), R^(i) and R^(j) is independently Hor lower alkyl;

[0141] when p is 1, 2, 3, 4, or 5, A₄ is N(R^(k)), C(R^(h))(R^(i)), orO; and when p is 0, A₄ is N(R^(k))(R^(i)), C(R^(h))(R^(i))(R^(j)), andO(R^(i)), where each R^(h), R^(i) and R^(j) is independently H or loweralkyl, each R^(k) is H, alkyl, aryl, or acyl, and each R^(l) is H,alkyl, or aryl;

[0142] provided that no more than two heteroatoms occur consecutively inthe above-depicted ring formed by A₁, (A₂)_(m), (A₃)_(p), A₄, and C═O,where each dotted line in the ring depicts a single bond when A₂ ispresent and a hydrogen atom when A₂ is absent;

[0143] R^(d) is H, halogen, hydroxyl or an alkyl, alkoxy or alkylthiogroup, where the alkyl, alkoxy or alkylthio group is unsubstituted orsubstituted with one or more suitable substituents;

[0144] R^(b) is H or an alkyl group, unsubstituted or substituted withone or more suitable substituents;

[0145] R^(e) is H, halogen, hydroxyl or an alkyl, alkoxy or alkylthiogroup, where the alkyl, alkoxy or alkylthio group is unsubstituted orsubstituted with one or more suitable substituents;

[0146] Z and Z¹ are each independently H, F, an alkyl, cycloalkyl,heterocycloalkyl, aryl or heteroaryl group, where the alkyl, cycloalkyl,heterocycloalkyl, aryl or heteroaryl group is unsubstituted orsubstituted with one or more suitable substituents, —C(O)R^(n) —CO₂R^(n)—CN, —C(O)NR^(n)R^(o), —C(O)NR^(n)OR^(o), —C(S)R^(n), —C(S)OR^(n)—C(S)NR^(n)R^(o), —C(═NR^(n))R^(o), —C(═NR^(n))OR^(o), —NO₂, —SOR^(o),—SO₂R^(n), —SO₂NR^(n)R^(o), —SO₂(NR^(n))(OR^(o)), —SONR^(n), —SO₃R^(n),—PO(OR^(n))₂, —PO(OR^(n))(OR^(o)), —PO(NR^(n)R^(o))(OR^(p)).—PO(NR^(n)R^(o))(NR^(p)R^(q)), —C(O)NR^(n)NR^(o)R^(p),—C(S)NR^(n)NR^(o)R^(p), where R^(n), R^(o), R^(p) and R^(q) are eachindependently H or an alkyl, cycloalkyl, aryl, heterocycloalkyl, acyl orthioacyl group, where the alkyl, cycloalkyl, aryl, heterocycloalkyl,acyl or thioacyl group is unsubstituted or substituted with one or moresuitable substituents, or where any two of the R^(n), R^(o), R^(p) andR^(q), taken together with the atoms to which they are bonded, form aheterocycloalkyl group, which may be optionally substituted,

[0147] or Z and R^(d), together with the atoms to which they are bonded,form a cycloalkyl or heterocycloalkyl group, where Z and R^(d) are asdefined above except for moieties that cannot form the cycloalkyl orheterocycloalkyl group,

[0148] or Z and Z¹, together with the atoms to which they are bonded,form a cycloalkyl or heterocycloalkyl group, where Z and Z¹ are asdefined above (except for moieties that cannot form the cycloalkyl orheterocycloalkyl group);

[0149] or a prodrug, pharmaceutically acceptable salt, pharmaceuticallyactive metabolite, or pharmaceutically acceptable solvate thereof.

[0150] In another aspect, the invention provides a method of interferingwith or preventing SARS related coronavirus viral replication activitycomprising contacting a SARS related coronavirus protease with atherapeutically effective amount of a rhinovirus 3C protease inhibitorof formula IV:

[0151] wherein:

[0152] Y is —N(R_(y))—, —C(R_(y))(R_(y))—, or —O—, where each R_(y) isindependently H or lower alkyl;

[0153] R₁ is H, F, an alkyl group, OH, SH, or an O-alkyl group;

[0154] R₂ and R₃ are each independently H;

[0155] where n is an integer from 0 to 5, A₁ is CH or N, A₂ and each A₃are independently selected from C(R₄₁)(R₄₁), N(R₄₁), S, S(O), S(O)₂, andO, and A₄ is NH or NR₄₁, where each R₄₁ is independently H or loweralkyl, provided that no more than 2 heteroatoms occur consecutively inthe ring formed by A₁, A₂, (A₃)_(n), A₄ and C═O; and provided that atleast one of R₂ and R₃ is

[0156] R₅ and R₆ are each independently H, F, an alkyl group, acycloalkyl group, a heterocycloalkyl group, an aryl group, or aheteroaryl group;

[0157] R₇ and R₈ are each independently H, an alkyl group, a cycloalkylgroup, a heterocycloalkyl group, an aryl group, a heteroaryl group,—OR₁₇, —SR₁₇, —NR₁₇R₁₈, —NR₁₉NR₁₇R₁₈, or —NR₁₇OR₁₈, where R₁₇, R₁₈, andR₁₉ are each independently H, an alkyl group, a cycloalkyl group, aheterocycloalkyl group, an aryl group, a heteroaryl group, or an acylgroup;

[0158] R₉ is a five-membered heterocycle having from one to threeheteroatoms selected from O, N, and S, or R₉ is

[0159] where R₂ is

[0160] and

[0161] Z and Z₁ are each independently H, F, an alkyl group, acycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroarylgroup, —C(O)R₂₁, —CO₂R₂₁, —CN, —C(O)NR₂₁R₂₂, —C(O)NR₂₁R₂₂, —C(S)R₂₁,—C(S)NR₂₁R₂₂, —NO₂, —SOR₂₁, —SO₂R₂₁, —SO₂NR₂₁R₂₂, —SO(NR₂₁)(OR₂₂),—SONR₂₁, —SO₃R₂₁, —PO(OR₂₁)₂, —PO(R₂₁)(R₂₂), —PO(NR₂₁R₂₂)(OR₂₃),PO(NR₂₁R₂₂)(NR₂₃R₂₄), —C(O)NR₂₁NR₂₂R₂₃, or —C(S)NR₂₁NR₂₂R₂₃, where R₂₁,R₂₂, R₂₃, and R₂₄ are each independently H, an alkyl group, a cycloalkylgroup, a heterocycloalkyl group, an aryl group, a heteroaryl group, anacyl group, or a thioacyl group, or any two of R₂₁, R₂₂, R₂₃, and R₂₄,together with the atom(s) to which they are bonded, form aheterocycloalkyl group, provided that Z and Z₁ are not both H;

[0162] or Z₁ and R₁, together with the atoms to which they are bonded,form a cycloalkyl or heterocycloalkyl group;

[0163] or Z and Z₁, together with the atoms to which they are bonded,form a cycloalkyl or heterocycloalkyl group;

[0164] or a prodrug, pharmaceutically active metabolite,pharmaceutically acceptable salt, or solvate thereof.

[0165] In another aspect, the invention provides a method of interferingwith or preventing SARS related coronavirus viral replication activitycomprising contacting a SARS related coronavirus protease with atherapeutically effective amount of a rhinovirus 3C protease inhibitorof the formula V[S11]:

[0166] wherein:

[0167] Y is —N(R^(y))—, —C(R^(y))(R^(y))—, or —O—, where each R^(y) isindependently H or lower alkyl;

[0168] R¹ is selected from optionally substituted alkyl, cycloalkyl,heterocycloalkyl, aryl, heteroaryl, and —C(O)R¹⁶, where R¹⁶ is selectedfrom optionally substituted alkyl, cycloalkyl, heterocycloalkyl, aryl,heteroaryl, alkoxy, cycloalkoxy, heterocycloalkoxy, aryloxy,heteroaryloxy, and amine;

[0169] R² and R⁸ are each independently selected from H, F, andoptionally substituted alkyl, cycloalkyl, heterocycloalkyl, aryl, andheteroaryl;

[0170] R³ and R⁹ are each independently selected from H and optionallysubstituted alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl,—OR¹⁷,—SR¹⁷, —NR¹⁷R¹⁸, —NR¹⁹NR¹⁷R¹⁸, and —NR¹⁷OR¹⁸, where R¹⁷,

[0171] R¹⁸, and R¹⁹ are each independently selected from H, alkyl,cycloalkyl, heterocycloalkyl, aryl, heteroaryl, and acyl;

[0172] R⁴is a suitable organic moiety;

[0173] each of R⁵, R⁶ and R⁷is independently H, F, or lower alkyl;

[0174] m is 0 or 1;

[0175] p is 0, 1, 2, 3, 4, or 5;

[0176] A₁ is CH or N;

[0177] when m is 1, A₂ is selected from C(R¹⁰)(R¹¹), N(R¹²), S, S(O),S(O)₂, and O;

[0178] when p is not 0, each A₃ is independently selected fromC(R¹⁰)(R¹¹), N(R¹²), S, S(O), S(O)₂, and O;

[0179] where R¹⁰, R¹¹ and R¹² are each independently H or lower alkyl;

[0180] when p is not 0, A₄ is selected from N(R¹³), C(R¹⁰)(R¹¹), and O,and when p is 0, A₄ is selected from N(R¹³)(R¹⁴), C(R¹⁰)(R¹¹)(R¹²), andO(R¹⁴), provided that when A₄ is O(R¹⁴), A₁ is not CH; where R¹⁰, R¹¹and R¹² are each independently H or lower alkyl, R¹³ is H, alkyl, aryl,or acyl, and R¹⁴ is H, alkyl, or aryl;

[0181] provided that A₁, (A₂)_(m), (A₃)_(p), and A₄ together do notinclude more than two consecutive heteroatoms;

[0182] or a prodrug, pharmaceutically acceptable salt, pharmaceuticallyactive metabolite, or pharmaceutically acceptable solvate thereof.

[0183] In another aspect, the invention provides a method of interferingwith or preventing SARS related coronavirus viral replication activitycomprising contacting a SARS related coronavirus protease with atherapeutically effective amount of a rhinovirus 3C protease inhibitorof formula VI:

[0184] wherein:

[0185] R^(a) is an alkylcarbonylalkyl, cycloalkylcarbonylalkyl,arylcarbonylalkyl, heteroarylcarbonylalkyl, alkylcarbonylaminoalkyl,cycloalkylcarbonylaminoalkyl, heterocycloalkylcarbonylaminoalkyl,arylcarbonylaminoalkyl, heteroarylcarbonylaminoalkyl,alkylaminocarbonylalkyl, cycloalkylaminocarbonylalkyl,heterocycloalkylaminocarbonylalkyl, arylaminocarbonylalkyl,heteroarylaminocarbonylalkyl group, where each alkyl, cycloalkyl,heterocycloalkyl, aryl and heteroaryl moiety thereof may beunsubstituted or substituted with one or more suitable substituents;

[0186] R^(b) is H or an alkyl group, unsubstituted or substituted withone or more suitable substituents;

[0187] R^(d) is H, halo, hydroxyl, or an alkyl, alkoxy or alkylthiogroup, where the alkyl, alkoxy or alkylthio group is unsubstituted orsubstituted with one or more suitable substituents;

[0188] R^(c) is a moiety having the formula:

[0189] R^(e) and R^(f) are each independently H or a lower alkyl group;

[0190] m is 0 or 1, provided that when m is 1, R^(a) is not anamino-substituted alkylcarbonylalkyl or amino-substitutedalkylcarbonylaminoalkyl group, and when m is 0, R^(a) is selected froman alkylaminocarbonylalkyl, cycloalkylaminocarbonylalkyl,heterocycloalkylaminocarbonylalkyl, arylaminocarbonylalkyl,heteroarylaminocarbonylalkyl and heteroarylcarbonylaminoalkyl group,provided that R^(a) is not substituted indolecarbonylaminoalkyl;

[0191] p is an integer of from 0 to 5;

[0192] A₁ is CH or N;

[0193] when p is 1, 2, 3, 4, or 5, A₂ is C(R^(g))(R^(h)), N(R^(i)), S,S(O), S(O)₂, or O, and when p is 0, A₂ is C(R^(g))(R^(h))(R^(i)),N(R^(g))(R^(i)), S(R^(g)), S(O)(R^(g)), S(O)₂(R^(g)), or O(R^(g)), whereeach R^(g), R^(h) and R^(i) is independently H or a lower alkyl group;

[0194] each A₃ present is independently C(R^(g))(R^(h)), N(R^(i)), S,S(O), S(O)₂, or O, where each R^(g), R^(h) and R^(i) is independently Hor a lower alkyl group;

[0195] when p is 1, 2, 3, 4, or 5, A₄ is N(R^(j)), C(R^(g))(R^(h)), orO, and when p is 0, A₄ is N(R^(j))(R^(k)), C(R^(g))(R^(h))(R^(i)), andO(R^(k)), where each R^(g), R^(h) and R^(i) is independently H or alower alkyl group, each R^(j) is H, an alkyl, aryl, or acyl group, andeach R^(k) is H or an alkyl or aryl group;

[0196] provided that no more than two heteroatoms occur consecutively inthe above-depicted ring formed by A₁, (A₂)_(m), (A₃)_(p), A₄, and C═O,where each dotted line in the ring depicts a single bond when A₂ ispresent and a hydrogen atom when A₂ is absent; and

[0197] Z and Z¹ are each independently H, F, an alkyl, cycloalkyl,heterocycloalkyl, aryl or heteroaryl group, where the alkyl, cycloalkyl,heterocycloalkyl, aryl or heteroaryl group is unsubstituted orsubstituted with one or more suitable substituents, —C(O)R^(l),—CO₂R^(l), —CN, —C(O)NR^(l)R_(m), —C(O)NR^(l)OR^(m), —C(S)R^(l),—C(S)OR^(l) —C(S)NR^(l)R^(m), —C(═NR^(l))R^(m), —C(═NR^(l))OR^(m), —NO₂,—SOR^(m), —SO₂R^(l), —SO₂NR^(l)R^(m), —SO₂(NR^(l))(OR^(m)), —SONR^(l),—SO₃R^(l), —PO(OR^(l))₂, —PO(OR^(l))(OR^(m)), —PO(NR^(l)R^(m))(OR^(n)),—PO(NR^(l)R^(m))(NR^(n)R^(o)), —C(O)NR^(l)NR^(m)R^(n),—C(S)NR^(l)NR^(m)R^(n), where R^(l), R^(m), R^(n) and R^(o) are eachindependently H or an alkyl, cycloalkyl, aryl, heterocycloalkyl, acyl orthioacyl group, where the alkyl, cycloalkyl, aryl, heterocycloalkyl,acyl or thioacyl group is unsubstituted or substituted with one or moresuitable substituents, or where any two of the R^(l), R^(m), R^(n) andR^(o), taken together with the atoms to which they are bonded, form aheterocycloalkyl group, which may be optionally substituted,

[0198] or Z and R^(d),together with the atoms to which they are bonded,form a cycloalkyl or heterocycloalkyl group, where Z and R^(d) are asdefined above except for moieties that cannot form the cycloalkyl orheterocycloalkyl group,

[0199] or Z and Z¹, together with the atoms to which they are bonded,form a cycloalkyl or heterocycloalkyl group, where Z and Z¹ are asdefined above;

[0200] or a prodrug, pharmaceutically acceptable salt, pharmaceuticallyactive metabolite, or pharmaceutically acceptable solvate of saidcompound.

[0201] In another aspect, the invention provides a method of interferingwith or preventing SARS related coronavirus viral replication activitycomprising contacting a SARS related coronavirus protease with atherapeutically effective amount of a rhinovirus 3C protease inhibitorof formula VII:

[0202] or a prodrug, pharmaceutically acceptable salt, orpharmaceutically acceptable solvate thereof.

[0203] In another aspect, the invention provides a method of interferingwith or preventing SARS related coronavirus viral replication activitycomprising contacting a SARS related coronavirus protease with atherapeutically effective amount of a rhinovirus 3C protease inhibitorof formula VIIA:

[0204] wherein:

[0205] R^(a) is substituted or unsubstituted heterocycloalkyl orheterocycloalkylalkyl;

[0206] R^(b) is a substituent having the formula:

[0207] wherein:

[0208] R^(f) and R^(g) are independently H or lower alkyl;

[0209] m is 1;

[0210] p is an integer of from 1 to 5;

[0211] A₁ is CH or N;

[0212] A₂ is C(R^(h))(R^(i)), N(R^(j)), S, S(O), S(O)₂, or O; where eachR^(h), R^(i) and R^(j) is independently H or lower alkyl;

[0213] each A₃ present is independently C(R^(h))(R^(i)), N(R^(j)), S,S(O), S(O)₂, or O; where each R^(h), R^(i) and R^(j) is independently Hor lower alkyl;

[0214] A₄ is N(R^(k)), C(R^(h))(R^(i)), or O;

[0215] provided that no more than two heteroatoms occur consecutively inthe above-depicted ring formed by A₁, (A₂)_(m), (A₃)_(p), A₄, and C═O,where each dotted line in the ring depicts a single bond;

[0216] R^(c) is H, halogen or a substituted or unsubstituted lower alkylgroup;

[0217] R^(d) is H, halogen, hydroxyl, a substituted or unsubstitutedalkyl, alkoxy or alkylthio group;

[0218] R^(e) is H or a substituted or unsubstituted alkylgroup; and

[0219] Z and Z¹ are independently H, F, a unsubstituted or substitutedalkyl group, cycloalkyl group, heterocycloalkyl group, aryl group orheteroaryl group, —C(O)R^(n), —CO₂R^(n), —CN, —C(O)NR^(n)R^(o),—C(O)NR^(n)OR^(o), —C(S)R^(n), —C(S)OR^(n), —C(S)NR^(n)R^(o), —NO₂,—SOR^(o), —SO₂R^(n), —SO₂NR^(n)R^(o), —SO₂(NR^(n))(OR^(o)), —SONR^(n),—SO₃R^(n), —PO(OR^(n))₂, —PO(OR^(n))(OR^(o)), —PO(NR^(n)R^(o))(OR^(p)),—PO(NR^(n)R^(o))(NR^(p)R^(q)), —C(O)NR NR^(o)R^(p), or —C(S)NRNR^(o)R^(p), wherein R^(n), R^(o), R^(p) and R^(q) are independently H,a substituted or unsubstituted alkyl group, cycloalkyl group, arylgroup, heterocycloalkyl group, acyl group or thioacyl group, or whereinany two of the R^(n), R^(o), R^(p) and R^(q), taken together with theatoms to which they are bonded, form a heterocycloalkyl group, which maybe optionally substituted,

[0220] or Z and R^(d), together with the atoms to which they are bonded,form a cycloalkyl or heterocycloalkyl group,

[0221] or Z and Z¹, together with the atom to which they are bonded,form a cycloalkyl or heterocycloalkyl group;

[0222] or a prodrug, pharmaceutically acceptable salt, orpharmaceutically acceptable solvate thereof.

[0223] In another aspect, the invention provides a method of interferingwith or preventing SARS related coronavirus viral replication activitycomprising contacting a SARS related coronavirus protease with atherapeutically effective amount of a rhinovirus 3C protease inhibitorselected from the group consisting of:

[0224] and the pharmaceutically acceptable salt, pharmaceutically activemetabolite, or solvate thereof.

[0225] In still another embodiment of the present invention, the methoddescribed above utilizes the rhinovirus inhibitor selected from thegroup consisting of:

[0226] 2-(2-Phenylethyl)benzoic acid N-hydroxyamide;

[0227] 2-(Propylthio)-pyridine-3-N-(hydroxy)carboxamide;

[0228][4-(N-Hydroxyamino)-2R-isobutyl-3S-((thien-2-yllthio)methyl)succinyl]-L-phenylalanine-N-methylamide;

[0229] N-Hydroxy-5-phenylpentanamide;

[0230] 2-(Phenyl-2-ethyl)pyridine-3-N-hydroxycarboxamide;

[0231] 2-(Thiobenzyl)benzoic acid N-hydroxy amide;

[0232]6-Biphenyl-4-yl-[2,2-dimethyl-1-(pyridin-4-ylcarbamoyl)-propylcarbamoyl]-hexanoicacid, N-hydroxyamide;

[0233] 3R(6-(4-Biphenyl)-3-(N-benzylcarbamoyl))-hexanoic acidN-hydroxyamide;

[0234] 2-Benzylsulfonyl-cyclopent-1-ene-carboxylic acid hydroxamide;

[0235] 2-Benzylsulfonyl-cyclohex-1-enecarboxylic acid hydroxyamide;

[0236] 6-Benzylsulfonyl-cyclohex-1-enecarboxylic acid hydroxyamide;

[0237] 1-(N-Hydroxy)-3-(2-bibenzyl)urea;

[0238] 3R-(6-(4-Biphenyl)propyl)-N-(3-methylpyridinecarbamoyl)-hexanoicacid N-hydroxy-amide;

[0239]4-(2-{[5-Hydroxyamino-3-(3-phenyl-propyl)-3,4-dihydro-2-H-pyrrole-3-carbonyl]-amino}-4-methyl-pentanoylamino)benzoicacid methyl ester;

[0240]5-Hydroxyamino-3-(3-phenyl-propyl)-3,4-dihydro-2-H-pyrrole-3-carboxylicacid (2-cyclohexyl-1-methylcarbamoyl-ethyl) amide;

[0241]4-(2-{[5-Hydroxyamino-3-(3-pentyl)-3,4-dihydro-2-H-pyrrole-3-carbonyl]-amino}-4-methyl-pentanoylamino)benzoic acid methyl ester;

[0242]6-Biphenyl-4-yl-3-(R)-(2-hydroxy-1-hydroxymethyl-ethylcarbamoyl)-hexanehydroxamicacid;

[0243]6-Biphenyl-4-yl-3(R)-(1(S)-hyroxymethyl-2,2-dimethyl-propylcarbamoyl)-hexanehydroxamicacid;

[0244] 2-(Biphenyl-4-ylsulfonyl)-cyclohex-1-enecarboxylic acidhydroxyamide;

[0245] 6-(Biphenyl-4-ylsulfonyl)-cyclohex-1-enecarboxylic acidhydroxyamide;

[0246] 2-Phenethylsulfanyl-cyclohex-I-enecarboxylic acid hydroxyamide;

[0247] 2-Benzylsulfanyl-cyclohexancarboxylic acid hydroxamide;

[0248] trans-2-Benzylsulfanyl-cyclohexancarboxylic acid hydroxamide;

[0249] trans-2-(Biphenyl-4-yl-methylsulfanyl)-cyclohexancarboxylic acidhydroxamide;

[0250]6-Biphenyl-4-yl-3-(R)-(1-hydroxymethyl-2-(S)-(1H-imidazol-4-yl)-ethylcarbamoyl)-hexanehydroxamicacid;

[0251]N-Hydroxy-2-[2-Oxo-3-(3-phenyl-propyl)-tetrahydro-furan-3-yl]-acetamide;

[0252] trans-2-(4-Phenoxy-benzylsulfanyl)-cyclohexancarboxylic acidhydroxamide;

[0253] 2-(4-Indol-1-yl-benzylsulfanyl)-cyclohexancarboxylic acidhydroxamide;

[0254]2-(3-Biphenyl-4-yl-propyl)-N4-hydroxy-N1-(2,4,5-trihydroxy-6-hydroxymethyl-tetrahydro-pyran-3-yl)-succinamide;

[0255] 2-(2-Biphenyl-4-yl-ethylsulfanyl)-cyclohexane carboxylic acidhydroxyamide;

[0256] 2-(3-Biphenyl-4-yl-propyl)-N4-hydroxy-N1-(2-hydroxy-cyclohexyl)-succinamide;

[0257] 6-Biphenyl-4-yl-3-(1-hydroxyimino-ethyl)-hexanoic acidhydroxyamide;

[0258]3-(R)-(2-Hydroxy-1-(S)-(1H-imidazol-4-yl)-ethylcarbamoyl)-6-(4-(2-methyl-thiazol-4-yl)-phenyl)-hexanehydroxamicacid;

[0259] 6-Biphenyl-4-yl-3-(3-hydroxy-piperidine-1-carbonyl)-hexanoicacid-hydroxyamide;

[0260] 1-(4-Methoxy-benzenesulfonyl)-piperidine-2-carboxylic acidhydroxamide;

[0261] 1-1-[4-Bromo-phenoxy)-benzenesulfonyl)-piperidine-2-carboxylicacid hydroxyamide;

[0262] N-(1-benzyl-2-hydroxy-ethyl)-N4-hydroxy-2-isobutyl-succinamide;

[0263]6-Biphenyl-4-yl-3(R)-2(S)-hydroxy-(1(S)-hydroxymethyl-2,2-dimethyl-propylcarbamoyl)-hexanoichydroxamic acid;

[0264]6-Biphenyl-4-yl-3-(2-hydroxy-1-hydroxmethyl-propylcarbamoyl)-hexanoichydroxamic acid;

[0265] trans-2-(3-Biphenyl-4-yl-propyl)-cyclohexane carboxylic acidhydroxyamide;

[0266] 1-[4-Biphenyl-4-yloxy)-benzenesulfonyl)-piperidine-2-carboxylicacid hydroxamide;

[0267] 1-(4-Phenoxy-benzenesulfonyl)-piperidine-2-carboxylic acidhydroxamide;

[0268]6-Biphenyl-4-yl-3-(R)-(1-(S)-hydroxymethyl-2-(3-pyridyl)-ethylcarbamoyl)-hexanehydroxamicacid;

[0269]6-Biphenyl-4-yl-2S-hydroxy-3R-(1S-hydroxymethyl-3-methylsulfanyl-propylcarbamoyl)-hexanoichydroxamic acid;

[0270]1-[-[4-(4-Bromo-phenoxy)-benzenesulfonyl]-4-(tertbutoxyarbonyl)-piperazine-2-carboxylicacid hydroxyamide;

[0271] 1-[4-(4-Bromo-phenoxy)-benzenesulfonyl]-piperazine-2-carboxylicacid hydroxyamide;

[0272] 4-Acetyl-1-[4-phenoxy-benzenesulfonyl]-piperazine-2-carboxylicacid, N-hydroxyamide;

[0273] 1-(Diphenylphosphinic)-piperidine-2-carboxylic acid hydroxamide;

[0274]6-Biphenyl-4-yl-3-(R)-(2-oxo-1-tetrahydrofuran-3-(S)-ylcarbamoyl)-hexanehydroxamic acid;

[0275]1-[-[4-(4-Bromo-phenoxy)-benzenesulfonyl]-4-methyl-piperazine-2-carboxylicacid N-hydroxyamide;

[0276] 4-(4-Methoxy-benzenesulfonyl)-thiomorpholine-3-carboxylic acidhydroxyamide;

[0277] 3-(Diphenylphosphinic)-propanoic acid hydroxyamide;

[0278]1-[4-(4-Chlorophenoxy)benzenesulfonyl]-thiomorpholine-3-carbamoyl)piperazine-2-carboxamide;

[0279] 4[4-Phenoxy-benzenesulfonyl]-piperazine-2-carboxylic acid,N-hydroxyamide;

[0280] 4[4-Phenoxy-benzenesulfonyl]-thiomorpholine-3-carboxylic acidN-hydroxyamide;

[0281] 3[2-Biphenyl-4-yl-ethylsulfanyl]-tetrahydro-pyran-4-carboxylicacid N-hydroxyamide;

[0282] 1-[4-Phenoxy-benzenesulfonyl]-4-methyl-piperazine-2-carboxylicacid N-hydroxyamide;

[0283] 6-Biphenyl-4-yl-3-(R)-(2-oxo-azepan-3-(S)-ylcarbamoyl)-hexanehydroxamic acid;

[0284] 4-(1H-Indole-2-sulfonyl)-thiomorpholine-3-carboxylic acidhydroxyamide;

[0285] 1-(Methyl-phenylphosphinic)-piperidine-2-(R)-carboxylic acidhydroxamide;

[0286] 1-(1,3-Dihydro-isoindole-2-sulfonyl)-piperidine-2-carboxylic acidhydroxamide;

[0287]4-Methyl-1-(4-(4-chlorophenyl)benzenesulfonyl)-N-hydroxy-2R-piperazinecarboxamidehydrochloride;

[0288]1-[4-Chlorophenoxybenzenesulfonyl]-N-hydroxy-2R-piperazinecarboxamide;

[0289] 2-(3-Phenyl-propylsulfonyl)-cyclohexane carboxylic acidhydroxamide;

[0290] 1-(Pyrolidine-1-sulfonyl)-piperidine-2-carboxylic acidhydroxyamide;

[0291] 1-(Piperidine-1-sulfonyl)-piperidine-2-carboxylic acidhydroxyamide;

[0292]4-[-[4-Bromo-phenoxy-benzenesulfonyl]-oxothiomorpholine-3-carboxylicacid-N-hydroxyamide;

[0293]1-[4-(4-Methoxy-phenylsulfanyl)-benzenesulfonyl]-piperdine-2-carboxylicacid hydroxyamide;

[0294]1-[4-(4-Cyano-phenoxy)-benzenesulfonyl]-4-(tert-butoxycarbonyl)-piperazine-2-carboxylicacid N-hydroxyamide;

[0295]6-Oxo-3-(4-phenoxy-benzenesulfonyl)-hexahydro-pyrimidine-4-carboxylicacid hydroxamate;

[0296]4-(t-Butoxycabonyl)-1-(4-(pyridin-2-yl)oxybenzensulfonyl)-N-hydroxy-piperazine-2-carboxamide;

[0297] 4-[(4-Fluorophenoxy)-benzenesulfonyl]-thiomorpholine-3-carboxylicacid N-hydroxyamide;

[0298]4-[4-(Fluoro-phenoxy)-benzenesulfonyl]-oxothiomorpholine-3-carboxyticacid N-hydroxyamide;

[0299] 4-(4-Butoxy-benzenesulfonyl)-thiomorpholine-3-carboxylic acidhydroxyamide;

[0300] 4-(4-Butoxy-benzenesulfonyl)-1-oxothiomorpholine-3-carboxylicacid hydroxyamide;

[0301]1-[4-(4-Fluorophenyl)benzenesulfonyl]-4-(tert-butoxycarboxyl)2R-piperazine-2-carboxylicacid hydroxyamide;

[0302]1-((4-(4-Chlorophenyl)-piperazine)-1-sulfonyl)-piperidine-2carboxylicacid hydroxamide;

[0303] cis-2-Phenethylsulfanyl-cyclohexanecarboxylic acid hydroxyamide;

[0304] 1-[-[4-(4-Fluorophenyl)benzenesulfonyl)-N-hydroxy-2R-piperazinecarboxamide hydrochoride;

[0305] 1-(Diphenylphosphinic)-pyrolidine-2(R)-carboxylic acidhydroxyamide;

[0306] trans-2-Phenethylsulfonyl-cyclohexanecarboxylic acidhydroxyamide;

[0307]1-[4-(4-Flourophenyl)-piperazine-1-sulfonyl]-piperidine-2-carboxylicacid hydroxamide;

[0308]1-1-[4-(4-Fluorophenylsulfanyl)-benzenesulfonyl]-piperidine-2-carboxylicacid hydroxyamide;

[0309]4-1-[4-(Bromo-phenoxy)-benzenesulfonyl]-2,2-dimethyl-1-oxo-thiomorpholine-3-carboxylicacid hydroxyamide;

[0310] 1-(Pyrrolidine-1-carbonyl)-pyrrolidine-2(R)-carboxylic acidhydroxyamide;

[0311]R-4-[4-(Bromophenoxy)-benzenesulfonyl]-2,2-dimethyl-1-oxo-thiomorpholine-3-carboxylicacid hydroxyamide;

[0312]4-(Ethoxycarbonyl)methyl-1-(4-(4-chlorophenyl)benzenesulfonyl)-N-hydroxy-2R-piperazinecarboxamidehydrochloride;

[0313] 1-Phenethylcarbamoyl-pyrrolidine-2-(R)-carboxylic acidhydroxyamide;

[0314] 1-(4-Benzyl-piperazine-1-sulfonyl)-piperidine-2-carboxylic acidhydroxyamide;

[0315] 3(S)-N-Hydroxy-4-(4-(pyridin-4-yl)oxybenzenesulfonyl)-2,2-dimethyl-tetrahydro-2H-1,4-thiazine-3-carboxamide;

[0316]2(R)4-Methyl-1-(4-(4-fluorophenyl)benzenesulfonyl)-N-hydroxy-piperazine-2-carboxamide;

[0317] 1-((2-Pyridyl)-4-piperazine-1-sulfonyl)-piperdine-2-carboxylicacid hydroxyamide;

[0318]1-1-[4-(Pyridin-4-ylsulfamyl)-benzenesulfonyl]-piperdine-2-carboxylicacid hydroxyamide;

[0319] N-(4-Phenoxy-benzenesulfonyl)-D-tert-leucine-N-hydroxyamide;

[0320]2,2-Dimethyl-4-[4-(pyridin-2-yloxy)-benzenesulfonyl]-thiomorpholine-3-carboxylicacid hydroxyamide;

[0321] N-1-[4-(4-Fluorophenoxyl) benzenesulfonyl)-D-tert-leucine,N-hydroxyamide;

[0322] 3(R)-N-Hydroxy4-(4-(pyridin-4-yl)oxybenzenesulfonyl)-2,2-dimethyl-tetrahydro-2H-1,4-thiazine-3-carboxamidehydrochloride;

[0323]2-[4-(4-Chloro-phenoxy)-benzenesulfonylamino]-N-hydroxy-3,3-dimethyl-butyramide;

[0324] 3(R)-N-Hydroxy-4-(4-(fur-3-yl) phenoxybenzenesulfonyl)-2,2-dimethyl-tetrahydro-2H-1,4-thiazine-3-carboxamide;

[0325]2-1-[4-(Pyridin-2-yl-oxy)-benzenesulfonylamino]-N-hydroxy-3,3-dimethylbutyramide;

[0326] 2-(2-Biphenyl-4-yl-ethylsulfonyl)-cyclohex-1-ene-carboxylic acidhydroxyamide;

[0327] 6-(2-Biphenyl-4-yl-ethyl sulfonyl)-cyclohex-1-ene-carboxylic acidhydroxyamide;

[0328]N-(4-Phenoxy-benzenesulfonyl)-3,3-dimethyl-S-(methylthio)-D-cysteine,N-hydroxyamide;

[0329] 1-(4-Phenoxy-piperidine-1-sulfonyl)-piperdine-2-carboxylic acidhydroxyamide;

[0330]N-(4-[4-Chlorophenoxy]-benzenesulfonyl)-3,3-dimethyl-S-(methylthio)-D-cysteine,N-hydroxyamide;

[0331]N-(4-[4-Chlorophenoxy]-benzenesulfonyl)-3,3-dimethyl-S-(methylsulfoxy)-D-cysteine,N-hydroxyamide;

[0332] cis-2-(2-Phenyl-ethanesulfonyl)-cyclohexanecarboxylic acidhydroxyamide;

[0333] 3(R)-N-Hydroxy-4-(4-(imidazol-1-yl)phenoxybenzenesulfonyl)-2,2-dimethyl-tetrahydro-2H-1,4-thiazine-3-carboxamide;

[0334] 3(R)-N-Hydroxy-4-(4-(pyridin-4-yl)oxybenzenesulfonyl)-2,2-dimethyl-tetrahydro-2H-1,4-thiazine-3-carboxamide;

[0335]4-1-[2-(2-Hydroxycarbamylmethyl-5-pheny-pentanoylamino)-4-methyl-pentanoyl]-benzoicacid methyl ester;

[0336] trans-2-(2-Phenyl-ethanesulfonyl)-cyclohexanecarboxylic acidhydroxyamide;

[0337] 3,3-Dimethyl-2-(4-phenoxy-phenylsulfanylmethyl)-butyric acid,N-hydroxyamide;

[0338] 2-(2-Biphenyl-4-yl-ethanesulfonyl)-cyclohexanecarboxylic acidhydroxamate;

[0339]2-[-[4-(4-Chlorophenyl)-piperazine-1-sulfonylamino]-3-methyl-3-(pyridin-2ylmethylsulfanyl)-butyricacid N-hydroxyamide;

[0340] 3,3-Dimethyl-2-(4-phenoxy-phenylsulfonylmethyl)-butyric acid,N-hydroxyamide;

[0341] 2(R)-[4-(4-Fluoro-phenoxy)benzenesulfonylamino]-3-methyl-3-(pyridin-2-yl sulfanyl)-butyric acid,hydroxyamide;

[0342] 3(R)-N-Hydroxy-4-(4-(-((pyridin-4-yl) methyl)oxybenzenesulfonyl)-2,2-dimethyl-tetrahydro-2H-1,4-thiazine-3-carboxamide;

[0343]1-1-[4-(4-Chloro-phenoxy)-benzenesulfonyl]-4-(1-methyl-H-imidazole-4-sulfonyl)-piperazine-2-carboxylicacid hydroxamide;

[0344]1-[4-(Pyridin-2-ylsulfanyl)-piperidine-1-sulfonyl]-piperidine-2-carboxylicacid hydroxyamide;

[0345]2R-[4-(4-Furan-3-yl-phenoxy)-benzenesulfonylamino]-N-hydroxy-3-methyl-3-(pyridin-4-ylsulfanyl)-butyramide;

[0346] trans-2-(2-Biphenyl-4-yl-ethylsu lfanyl)-cyclohexanecarboxylicacid hydroxyamide;

[0347] N4-(2,2-Dimethyl-1S-hydroxymethyl-propyl)-N1-hydroxy-3R[3-(4-pyridin-4-yl-phenyl)-pyrrol-1-yl]-succindiamide;

[0348]1-[4-(4-Fluoro-phenoxy)-benzenesulfonyl)]-3,3-dimethyl-5-oxo-piperazine-2-carboxylicacid hydroxyamide;

[0349]2(R)-[4-(4-lodo-phenoxy)benzenesulfonylamino]-3-methyl-(pyridin-3-yl-sulfonyl)butyric acid hydroxyamide;

[0350]1-[-[2-(Benzothiazol-2-ylsulfanyl)-piperidine-1-sulfonyl]piperidine-2-carboxylicacid hydroxyamide;

[0351] 5-[4-(4-Fluoro-phenoxy)-benzenesulfonyl]-4, 5, 6,7-tetrahydro-3H-imidazolo[4,5,-c]pyridine-6-carboxylic acidhydroxyamide;

[0352]1-[4-(Pyridin-4-ylsulfanyl)-piperidine-1-sulfanyl]-piperidine-2carboxylicacid hydroxyamide;

[0353]1-[4-(4-Methoxy-phenylsulfamyl)-piperidine-1-sulfonyl]piperidine-2-carboxylicacid hydroxyamide;

[0354]2(R)-[4-(4-Methylphenoxy)benzenesulfonylamino]-3-methyl-3-(pyrdin-3-yl-sulfonyl)butyric acid hydroxyamide;

[0355]1-[4-(4-Methyl-phenylsulfamyl)-piperidine-1-sulfonyl]-piperidine-2-carboxylicacid hydroxamide;

[0356]4-Methoxy-benzenesulfonyl)-2,2-dimethyl-thiomorpholine-3-carboxylic acidhydroxyamide;

[0357]4-1-[4-(4-Chloro-phenoxy)-benzenesulfonyl]-2,2-dimethyl-thiomorpholine-3-carboxylicacid hydroxyamide;

[0358] 2(R)-[4-(4-bromo-phenoxy)benzenesulfoxylamino]-3-methyl-3-(pyridin-4-yl-sulfoxide) butyric acidhydroxyamide;

[0359]4-(4-Methoxy-benzensulfonyl)-2,2-dimethyl-1-oxo-thiomorpholine-3-carboxylicacid hydroxyamide;

[0360]4-4-(4-Chloro-phenoxy)-benzenesulfonyl]-2,2-dimethoxy-1-oxo-thiomorpholine-3-carboxylicacid hydroxyamide;

[0361]3(S)-2,2-Dimethyl-4-[4-(pyridin-4-ylsulfanyl)-benzenesulfonyl]-thiomorpholine-3-carboxylicacid hydroxyamide;

[0362]3,3-Dimethyl-N-hydroxy-2R-[-[4(-(pyridin-4-ylsulfanyl)-piperidine-1-sulfonylamino]-butyramide;

[0363] N-Hydroxy-2-[-[(4-methylbenzenesulfonyl) amino]acetamide;

[0364][4(-(4-Imidazol-1-yl-phenoxy)-piperidine-1-sulfonyl]-piperidine-2-carboxylicacid hydroxyamide;

[0365]1-[4-(4-Imidazol-1-yl-phenylsulfanyl)-piperidine-1-sulfonyl]-piperidine-2-carboxylicacid hydroxyamide;

[0366]2(R)-[4-(4-Chloro-benzoyl)-cyclohexanesulfonyl]-piperidine-1-carboxylicacid hydroxyamide;

[0367]1(R)-[4-(4-Chloro-benzoyl)-piperidine-1-sulfonyl]-piperidine-2-carboxylicacid hydroxyamide;

[0368]1(R)-(4-Pyrdin-2-yl-piperazine-1-sulfonyl)-piperidine-2-carboxylic acidhydroxyamide;

[0369]1(R)-[4-(4-Imidazol-1-yl-phenoxy)-piperidine-1-sulfonyl]-piperidine-2-carboxylicacid hydroxyamide;

[0370]N-Hydroxy-3,3-dimethyl-2R-[4(-(morpholine-4-carbonyl)-piperidine-1-sulfonylamino]-butyramide;

[0371]N-Hydroxy-3-methyl-3-(5-methyl-isoxazol-3-yl-methylsulfanyl)-2R-[4-(pyridin-4-ylsulfanyl)-piperidine-sulfonylamino]-butyramide;

[0372]N-Hydroxy-2R-[4-(4-imidazol-1-yl-phenoxy)-piperidine-1-sulfonylamino]-3,3-dimethyl-butyramide;

[0373]2R-[4-(4-Chloro-benzoyl)-piperazine-1-sulfonylamino]-Nhydroxy-3-methyl-3-methylsulfanyl-butyramide;

[0374]N-Hydroxy-3-methyl-3-methylsulfanyl-2R-[4-(pydin-4--ylsonylamino]-butyramide;

[0375]1R,3S,2,2-Dimethyl-1-oxo-4-[-[4(-(pyridin-4-yloxy)-benzenesulfonyl]-thiomorpholine-3-carboxylicacidamide;

[0376]4-(2-(4-fluorobenzyl)-6-methyl-5-[(5-methylisoxazole-3-carbonyl)-amino]-4-oxoheptanoylamino-5-(2-oxopyrrolidin-3-yl)-pent-2-enoicacid ethyl ester; and the pharmaceutically acceptable salts thereof.

[0377] Other embodiments of the invention include those described inU.S. application Ser. Nos. 08/825331, 08/991282 (U.S. Pat. No.6,020,371), 09/421560 (U.S. Pat. No. 6,331,554), 09/947381 (Pub. No.0032237A-1), 09/567148 (U.S. Pat. No. 6,369,226), 09/882345 (Pub. No.0061916), 09/301977 (U.S. Pat. No. 6,531,452), 09/647712, 10/289982,09/631708 (U.S. Pat. No. 6,534,530), 09/834783 (Pub. No. 0006943-Al),and 09/726376 (U.S. Pat. No. 6,514,997), which are incorporated hereinin their entirety by reference.

BRIEF DESCRIPTION OF THE FIGURES

[0378]FIG. 1 is a sequence alignment of 3C-like protein translated fromSARS genome (AY274119) with TGEV 3C-like proteinase (1LVO) used forhomology modeling. The location of the first indel was adjusted from theBLAST alignment to better reflect the multiple alignment of othercoronavirus 3C-like proteins (Anand, Palm et al. 2002). 43% of theresidues are identical in this alignment.

[0379]FIG. 2 depicts the twelve residues used to superimpose the 3C-likeprotein structures were identified by visual inspection. They include aregion near the catalytic cysteine, the catalytic histidine, and aregion of structurally conserved beta-strand.

[0380]FIG. 3 is a homology model for SARS 3C-like protease (atom-colorwire) superimposed on the cocrystal structure of rhinovirus 3C protease(purple wire) bound to AG7088 (atom-color stick).

[0381]FIG. 4 shows the hydrogen bond between AG7088 and rhinovirus 3Cprotease from the cocrystal structure (1CQQ), the corresponding hydrogenbonds between AG7088 and the model of SARS 3C protease when superimposedon the structure of rhinovirus 3C protease. Four of the hydrogen bondspredicted between AG7088 and the SARS 3C protease model are also foundin the cocrystal structure of TGEV (1LVO), where water or the smallmolecule 2-methyl-2,4-pentanediol replace the inhibitor.

[0382]FIG. 5 shows solvent accessible (Connolly) surface of the bindingsite of AG7088 in the crystal structure of rhinovirus 3C protease (upperpanel) and the corresponding surface in the SARS 3C protease model(lower panel).

[0383]FIG. 6 shows the percent (%) identity between coronavirus 3Cproteases including SARS (AY274119), MHV: murine hepatitis virus(M55148), BCoV: bovine coronavirus (Q8V440), PEDV: porcine epidemicdiarrhea virus (Q91AV2), FIPV: feline infectious peritonitis virus(Q98VG9), TGEV: transmissible gastroenteritis virus (Q91W05), HCoV:human coronavirus 229E (Q9DLN0), AIBV: avian infectious bronchitis virus(M95169).

[0384]FIG. 7 is a phylogenetic tree describing the coronavirus 3Cproteases.

[0385]FIG. 8 is a molecular model of compound 1 in the binding site ofSARS 3C like protease.

[0386]FIG. 9 is a molecular model of compound 2 in the binding site ofSARS 3C like protease.

[0387]FIG. 10 is a molecular model of compound 3 in the binding site ofSARS 3C like protease.

[0388]FIG. 11 is a molecular model of compound 4 in the binding site ofSARS 3C like protease.

[0389]FIG. 12 is a molecular model of compound 5 in the binding site ofSARS 3C like protease.

[0390]FIG. 13 is a molecular model of compound 6 in the binding site ofSARS 3C like protease.

[0391]FIG. 14 is a molecular model of compound 7 in the binding site ofSARS 3C like protease.

[0392]FIG. 15 is a molecular model of compound 8 in the binding site ofSARS 3C like protease.

[0393]FIG. 16 is a molecular model of compound 9 in the binding site ofSARS 3C like protease.

[0394]FIG. 17 is a molecular model of compound 10 in the binding site ofSARS 3C like protease.

[0395]FIG. 18 is a molecular model of compound 11 in the binding site ofSARS 3C like protease.

[0396]FIG. 19 is a molecular model of compound 12 in the binding site ofSARS 3C like protease.

[0397]FIG. 20 is a molecular model of compound 13 in the binding site ofSARS 3C like protease.

[0398]FIG. 21 is a molecular model of compound 14 in the binding site ofSARS 3C like protease.

[0399]FIG. 22 is a molecular model of compound 15 in the binding site ofSARS 3C like protease.

[0400]FIG. 23 is a molecular model of compound 16 in the binding site ofSARS 3C like protease.

[0401]FIG. 24 is a molecular model of compound 17 in the binding site ofSARS 3C like protease.

[0402]FIG. 25 is a molecular model of compound 18 in the binding site ofSARS 3C like protease.

[0403]FIG. 26 is a molecular model of compound 19 in the binding site ofSARS 3C like protease.

[0404]FIG. 27 is a molecular model of compound 20 in the binding site ofSARS 3C like protease.

[0405]FIG. 28 is a molecular model of compound 21 in the binding site ofSARS 3C like protease.

[0406]FIG. 29 is a molecular model of compound 22 in the binding site ofSARS 3C like protease.

[0407]FIG. 30 is a molecular model of compound 23 in the binding site ofSARS 3C like protease.

[0408]FIG. 31 is a molecular model of compound 24 in the binding site ofSARS 3C like protease.

[0409]FIG. 32 is a molecular model of compound 25 in the binding site ofSARS 3C like protease.

[0410]FIG. 33 is a molecular model of compound 26 in the binding site ofSARS 3C like protease.

DETAILED DESCRIPTION OF THE INVENTION AND PREFERRED EMBODIMENTS

[0411] For purposes of the present invention, as described and claimedherein, the following terms are defined as follows:

[0412] As used herein, the terms “comprising” and “including” are usedin their open, non-limiting sense.

[0413] The term “alkyl”, as used herein, unless otherwise indicated,includes saturated monovalent hydrocarbon radicals having straight,branched, or cyclic moieties (including fused and bridged bicyclic andspirocyclic moieties), or a combination of the foregoing moieties. Foran alkyl group to have cyclic moieties, the group must have at leastthree carbon atoms.

[0414] A “lower alkyl” is intended to mean an alkyl group having from 1to 4 carbon atoms in its chain. The term “heteroalkyl” refers to astraight- or branched-chain alkyl group having from 2 to 12 atoms in thechain, one or more of which is a heteroatom selected from S, O, and N.Exemplary heteroalkyls include alkyl ethers, secondary and tertiaryamines, alkyl sulfides and the like.

[0415] The term “alkenyl”, as used herein, unless otherwise indicated,includes alkyl moieties having at least one carbon-carbon double bondwherein alkyl is as defined above and including E and Z isomers of saidalkenyl moiety.

[0416] The term “alkynyl”, as used herein, unless otherwise indicated,includes alkyl moieties having at least one carbon-carbon triple bondwherein alkyl is as defined above.

[0417] The term “carbocycle” refers to a saturated, partially saturated,unsaturated, or aromatic, monocyclic or fused or non-fused polycyclic,ring structure having only carbon ring atoms (no heteroatoms, i.e.,non-carbon ring atoms). Exemplary carbocycles include cycloalkyl, aryl,and cycloalkyl-aryl groups.

[0418] The term “heterocycle” refers to a saturated, partiallysaturated, unsaturated, or aromatic, monocyclic or fused or non-fusedpolycyclic, ring structure having one or more heteroatoms selected fromN, O, and S. Exemplary heterocycles include heterocycloalkyl,heteroaryl, and heterocycloalkyl-heteroaryl groups.

[0419] A “cycloalkyl group” is intended to mean a saturated or partiallysaturated, monocyclic, or fused or spiro polycyclic, ring structurehaving a total of from 3 to 18 carbon ring atoms (but no heteroatoms).Exemplary cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl,cyclopentenyl, cyclohexyl, cycloheptyl, adamantyl, and like groups.

[0420] A “heterocycloalkyl group” is intended to mean a monocyclic, orfused or spiro polycyclic, ring structure that is saturated or partiallysaturated, and has a total of from 3 to 18 ring atoms, including 1 to 5heteroatoms selected from nitrogen, oxygen, and sulfur. IllustrativeExamples of heterocycloalkyl groups include pyrrolidinyl,tetrahydrofuryl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl,aziridinyl, and like groups.

[0421] The term “aryl”, as used herein, unless otherwise indicated,includes an organic radical derived from an aromatic hydrocarbon byremoval of one hydrogen, such as phenyl or naphthyl.

[0422] The term “4-10 membered heterocyclic”, as used herein, unlessotherwise indicated, includes aromatic and non-aromatic heterocyclicgroups containing one to four heteroatoms each selected from O, S and N,wherein each heterocyclic group has from 4-10 atoms in its ring system,and with the proviso that the ring of said group does not contain twoadjacent O or S atoms. Non-aromatic heterocyclic groups include groupshaving only 4 atoms in their ring system, but aromatic heterocyclicgroups must have at least 5 atoms in their ring system. The heterocyclicgroups include benzo-fused ring systems. An example of a 4 memberedheterocyclic group is azetidinyl (derived from azetidine). An example ofa 5 membered heterocyclic group is thiazolyl and an example of a 10membered heterocyclic group is quinolinyl. Examples of non-aromaticheterocyclic groups are pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl,tetrahydrothienyl, tetrahydropyranyl, dihydropyranyl,tetrahydrothiopyranyl, piperidino, morpholino, thiomorpholino,thioxanyl, piperazinyl, azetidinyl, oxetanyl, thietanyl,homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl,thiazepinyl, 1,2,3,6-tetrahydropyridinyl, 2-pyrrolinyl, 3-pyrrolinyl,indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl,pyrazolinyl, dithianyl, dithiolanyl, dihydropyranyl, dihydrothienyl,dihydrofuranyl, pyrazolidinyl, imidazolinyl, imidazolidinyl,3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[4.1.0]heptanyl, 3H-indolyl andquinolizinyl. Examples of aromatic heterocyclic groups are pyridinyl,imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl,furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl,quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl,cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl,triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl,furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl,benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, andfuropyridinyl. The foregoing groups, as derived from the groups listedabove, may be C-attached or N-attached where such is possible. Forinstance, a group derived from pyrrole may be pyrrol-1-yl (N-attached)or pyrrol-3-yl (C-attached). Further, a group derived from imidazole maybe imidazol-1-yl (N-attached) or imidazol-3-yl (C-attached). An exampleof a heterocyclic group wherein 2 ring carbon atoms are substituted withoxo (═O) moieties is 1,1-dioxo-thiomorpholinyl.

[0423] A “heteroaryl group” is intended to mean a monocyclic or fused orspiro polycyclic, aromatic ring structure having from 4 to 18 ringatoms, including from 1 to 5 heteroatoms selected from nitrogen, oxygen,and sulfur. Illustrative Examples of heteroaryl groups include pyrrolyl,thienyl, oxazolyl, pyrazolyl, thiazolyl, furyl, pyridinyl, pyrazinyl,triazolyl, tetrazolyl, indolyl, quinolinyl, quinoxalinyl, benzthiazolyl,benzodioxinyl, benzodioxolyl, benzooxazolyl, and the like. The term“alkoxy”, as used herein, unless otherwise indicated, includes O-alkylgroups wherein alkyl is as defined above.

[0424] The term “amino” is intended to mean the —NH₂ radical. The term“halogen” represents chlorine, fluorine, bromine or iodine.

[0425] The term “halo”, as used herein, unless otherwise indicated,means fluoro, chloro, bromo or iodo. Preferred halo groups are fluoro,chloro and bromo.

[0426] The term “a pharmaceutically acceptable salt” refers to a saltthat retains the biological effectiveness of the free acids and bases ofthe specified compound and that is not biologically or otherwiseundesirable. A compound of the invention may possess a sufficientlyacidic, a sufficiently basic, or both functional groups, and accordinglyreact with any of a number of inorganic or organic bases, and inorganicand organic acids, to form a pharmaceutically acceptable salt. Exemplarypharmaceutically acceptable salts include those salts prepared byreaction of the compounds of the present invention with a mineral ororganic acid or an inorganic base, such as salts including sulfates,pyrosulfates, bisulfates, sulfites, bisulfites, phosphates,monohydrogenphosphates, dihydrogenphosphates, metaphosphates,pyrophosphates, chlorides, bromides, iodides, acetates, propionates,decanoates, caprylates, acrylates, formates, isobutyrates, caproates,heptanoates, propiolates, oxalates, malonates, succinates, suberates,sebacates, fumarates, maleates, butyne-1,4-dioates, hexyne-1,6-dioates,benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates,hydroxybenzoates, methoxybenzoates, phthalates, sulfonates,xylenesulfonates, phenylacetates, phenylpropionates, phenylbutyrates,citrates, lactates, γ-hydroxybutyrates, glycollates, tartrates,methane-sulfonates, propanesulfonates, naphthalene-1-sulfonates,naphthalene-2-sulfonates, and mandelates.

[0427] The term “substituted” means that the specified group or moietybears one or more substituents. The term “unsubstituted” means that thespecified group bears no substituents. The term “optionally substituted”means that the specified group is unsubstituted or substituted by one ormore substituents.

[0428] The term “SARS-inhibiting agent” means any rhinovirus proteaseinhibitor compound represented by formula I or a pharmaceuticallyacceptable salt, hydrate, prodrug, active metabolite or solvate thereof.Examples of rhinovirus protease inhibitors can be found in, but notlimited to, U.S. application Ser. Nos. 09/301977 and 09/726376, whichare incorporated herein in their entirety by reference.

[0429] The term “processes mediated by rhinovirus protease”, as usedherein, refers to biological, physiological, endocrinological, and otherbodily processes which are mediated by receptor or receptor combinationswhich are responsive to the rhinovirus inhibitors described herein(e.g., SARS-related virus). Modulation of such processes can beaccomplished in vitro or in vivo. In vivo modulation can be carried outin a wide range of subjects, such as, for example, humans, rodents,sheep, pigs, cows, and the like.

[0430] The term “interfering with or preventing” SARS-relatedcoronavirus (“SARS”) viral replication in a cell means to reduce SARSreplication or production of SARS components necessary for progeny virusin a cell as compared to a cell not being transiently or stablytransduced with the ribozyme or a vector encoding the ribozyme. Simpleand convenient assays to determine if SARS viral replication has beenreduced include an ELISA assay for the presence, absence, or reducedpresence of anti-SARS antibodies in the blood of the subject (Nasoff etal., PNAS 88:5462-5466, 1991), RT-PCR (Yu et al., in Viral Hepatitis andLiver Disease 574-477, Nishioka, Suzuki and Mishiro (Eds.);Springer-Verlag Tokyo, 1994). Such methods are well known to those ofordinary skill in the art. Alternatively, total RNA from transduced andinfected “control” cells can be isolated and subjected to analysis bydot blot or northern blot and probed with SARS specific DNA to determineif SARS replication is reduced. Alternatively, reduction of SARS proteinexpression can also be used as an indicator of inhibition of SARSreplication. A greater than fifty percent reduction in SARS replicationas compared to control cells typically quantitates a prevention of SARSreplication.

[0431] The term “pharmaceutically acceptable carrier” refers to acarrier or adjuvant that may be administered to a patient, together witha compound of this invention, and which does not destroy thepharmacological activity thereof and is nontoxic when administered indoses sufficient to deliver a therapeutic amount of the compound.

[0432] The term “prodrug” is a compound that may be converted underphysiological conditions or by solvolysis to the specified compound orto a pharmaceutically acceptable salt of such compound. A prodrug may bea derivative of one of the hydroxamate compounds of the presentinvention that contains a moiety, such as for example —CO₂R,—PO(OR)₂ or—C═NR, that may be cleaved under physiological conditions or bysolvolysis. Any suitable R substituent may be used that provides apharmaceutically acceptable solvolysis or cleavage product. A prodrugcontaining such a moiety may be prepared according to conventionalprocedures by treatment of a hydroxamate compound of this inventioncontaining, for example, an amido, carboxylic acid, or hydroxyl moietywith a suitable reagent.

[0433] The term “active metabolite” refers to a pharmacologically activeproduct produced through metabolism in the body of a specifiedhydroxamate compound or salt thereof.

[0434] Prodrugs and active metabolites of the inhibitor compoundsdescribed herein may be identified using routine techniques known in theart. See, e.g., Bertolini et al., J. Med. Chem., 40:2011-2016 (1997);Shan et al., J. Pharm. Sci., 86 (7):765-767 (1997); Bagshawe, Drug Dev.Res., 34:220-230 (1995); Bodor, Advances in Drug Res., 13:224-331(1984); Bundgaard, “Design of Prodrugs” (Elsevier Press, 1985); Larsen,Design and Application of Prodrugs, Drug Design and Development(Krogsgaard-Larsen et al. eds., Harwood Academic Publishers, 1991); Dearet al., Chromatogr. B, 748:281-293 (2000); Spraul et al., J.Pharmaceutical & Biomedical Analysis, 10 (8):601-605 (1992); and Prox etal., Xenobiol, 3(2):103-112 (1992).

[0435] The term “solvate” is intended to mean a pharmaceuticallyacceptable solvate form of a specified compound that retains thebiological effectiveness of such compound. Examples of solvates includecompounds of the invention in combination with water, isopropanol,ethanol, methanol, DMSO, ethyl acetate, acetic acid, or ethanolamine.

[0436] If an inhibitor compound used in the method of the invention is abase, a desired salt may be prepared by any suitable method known to theart, including treatment of the free base with an inorganic acid (suchas hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,phosphoric acid, and the like), or with an organic acid (such as aceticacid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonicacid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid,pyranosidyl acid (such as glucuronic acid or galacturonic acid),alpha-hydroxy acid (such as citric acid or tartaric acid), amino acid(such as aspartic acid or glutamic acid), aromatic acid (such as benzoicacid or cinnamic acid), sulfonic acid (such as p-toluenesulfonic acid orethanesulfonic acid), and the like.

[0437] If an inhibitor compound used in the method of the invention isan acid, a desired salt may be prepared by any suitable method known tothe art, including treatment of the free acid with an inorganic ororganic base (such as an amine (primary, secondary, or tertiary)), analkali metal hydroxide, or alkaline earth metal hydroxide. Illustrativeexamples of suitable salts include organic salts derived from aminoacids (such as glycine and arginine), ammonia, primary amines, secondaryamines, tertiary amines, and cyclic amines (such as piperidine,morpholine, and piperazine), as well as inorganic salts derived fromsodium, calcium, potassium, magnesium, manganese, iron, copper, zinc,aluminum, and lithium.

[0438] In the case of inhibitor compounds, prodrugs, salts, or solvatesthat are solids, it is understood by those skilled in the art that thehydroxamate compound, prodrugs, salts, and solvates used in the methodof the invention, may exist in different polymorph or crystal forms, allof which are intended to be within the scope of the present inventionand specified formulas. In addition, the hydroxamate compound, salts,prodrugs and solvates used in the method of the invention may exist astautomers, all of which are intended to be within the broad scope of thepresent invention.

[0439] In some cases, the inhibitor compounds, salts, prodrugs andsolvates used in the method of the invention may have chiral centers.When chiral centers are present, the hydroxamate compound, salts,prodrugs and solvates may exist as single stereoisomers, racemates,and/or mixtures of enantiomers and/or diastereomers. All such singlestereoisomers, racemates, and mixtures thereof are intended to be withinthe broad scope of the present invention.

[0440] As generally understood by those skilled in the art, an opticallypure compound is one that is enantiomerically pure. As used herein, theterm “optically pure” is intended to mean a compound comprising at leasta sufficient activity. Preferably, an optically pure amount of a singleenantiomer to yield a compound having the desired pharmacological purecompound of the invention comprises at least 90% of a single isomer (80%enantiomeric excess), more preferably at least 95% (90% e.e.), even morepreferably at least 97.5% (95% e.e.), and most preferably at least 99%(98% e.e.).

[0441] The term “treating”, as used herein, unless otherwise indicated,means reversing, alleviating, inhibiting the progress of, or preventingthe disorder or condition to which such term applies, or one or moresymptoms of such disorder or condition. The term “treatment”, as usedherein, unless otherwise indicated, refers to the act of treating as“treating” is defined immediately above. In a preferred embodiment ofthe present invention, “treating” or “treatment” means at least themitigation of a disease condition in a human, that is alleviated by theinhibition of the activity of one or more coronaviral 3C-like proteases,including, but not limited to the 3C-like protease of the causativeagent for SARS. In the case of SARS, representative disease conditionsinclude fever, dry cough, dyspnea, headache, hypoxemia, lymphopenia,elevated aminotransferase levels as well as viral titer. Methods oftreatment for mitigation of a disease condition include the use of oneor more of the compounds in the invention in any conventionallyacceptable manner. According to certain preferred embodiments of theinvention, the compound or compounds of the present invention areadministered to a mammal, such as a human, in need thereof. Preferably,the mammal in need thereof is infected with a coronavirus such as thecausative agent of SARS.

[0442] The present invention also includes prophylactic methods,comprising administering an effective amount of a compound of theinvention, or a pharmaceutically acceptable salt, prodrug,pharmaceutically active metabolite, or solvate thereof to a mammal, suchas a human, at risk for infection by a coronavirus. According to certainpreferred embodiments, an effective amount of one or more compounds ofthe invention, or a pharmaceutically acceptable salt, prodrug,pharmaceutically active metabolite, or solvate thereof is administeredto a human at risk for infection by the causative agent for SARS. Theprophylactic methods of the invention include the use of one or more ofthe compounds in the invention in any conventionally acceptable manner.

[0443] Recent evidence indicates that a new coronavirus is the causativeagent of SARS. The nucleotide sequence of the SARS-associatedcoronavirus has also recently been determined and made publicallyavailable.

[0444] The activity of the inhibitor compounds as inhibitors ofSARS-related viral activity may be measured by any of the suitablemethods available in the art, including in vivo and in vitro assays. Theactivity of the compounds of the present invention as inhibitors ofcoronavirus 3C-like protease activity (such as the 3C-like protease ofthe SARS coronavirus) may be measured by any of the suitable methodsknown to those skilled in the art, including in vivo and in vitroassays. Examples of suitable assays for activity measurements includethe antiviral cell culture assays described herein as well as theantiprotease assays described herein, such as the assays described inExamples 1 through 3.

[0445] Administration of the inhibitor compounds and theirpharmaceutically acceptable prodrugs, salts, active metabolites, andsolvates may be performed according to any of the accepted modes ofadministration available to those skilled in the art. IllustrativeExamples of suitable modes of administration include oral, nasal,pulmonary, parenteral, topical, transdermal, and rectal. Oral,intravenous, and nasal deliveries are preferred.

[0446] A SARS-inhibiting agent may be administered as a pharmaceuticalcomposition in any suitable pharmaceutical form. Suitable pharmaceuticalforms include solid, semisolid, liquid, or lyopholized formulations,such as tablets, powders, capsules, suppositories, suspensions,liposomes, and aerosols. The SARS-inhibiting agent may be prepared as asolution using any of a variety of methodologies. For example, theSARS-inhibiting agent can be dissolved with acid (e.g., 1 M HCl) anddiluted with a sufficient volume of a solution of 5% dextrose in water(D5W) to yield the desired final concentration of SARS-inhibiting agent(e.g., about 15 mM). Alternatively, a solution of D5W containing about15 mM HCl can be used to provide a solution of the SARS-inhibiting agentat the appropriate concentration. Further, the SARS-inhibiting agent canbe prepared as a suspension using, for example, a 1% solution ofcarboxymethylcellulose (CMC).

[0447] Acceptable methods of preparing suitable pharmaceutical forms ofthe pharmaceutical compositions are known or may be routinely determinedby those skilled in the art. For example, pharmaceutical preparationsmay be prepared following conventional techniques of the pharmaceuticalchemist involving steps such as mixing, granulating, and compressingwhen necessary for tablet forms, or mixing, filling, and dissolving theingredients as appropriate, to give the desired products for oral,parenteral, topical, intravaginal, intranasal, intrabronchial,intraocular, intraaural, and/or rectal administration.

[0448] Pharmaceutical compositions of the invention may also includesuitable excipients, diluents, vehicles, and carriers, as well as otherpharmaceutically active agents, depending upon the intended use. Solidor liquid pharmaceutically acceptable carriers, diluents, vehicles, orexcipients may be employed in the pharmaceutical compositions.Illustrative solid carriers include starch, lactose, calcium sulfatedihydrate, terra alba, sucrose, talc, gelatin, pectin, acacia, magnesiumstearate, and stearic acid. Illustrative liquid carriers include syrup,peanut oil, olive oil, saline solution, and water. The carrier ordiluent may include a suitable prolonged-release material, such asglyceryl monostearate or glyceryl distearate, alone or with a wax. Whena liquid carrier is used, the preparation may be in the form of a syrup,elixir, emulsion, soft gelatin capsule, sterile injectable liquid (e.g.,solution), or a nonaqueous or aqueous liquid suspension.

[0449] A dose of the pharmaceutical composition may contain at least atherapeutically effective amount of an SARS-inhibiting agent andpreferably is made up of one or more pharmaceutical dosage units. Theselected dose may be administered to a mammal, for example, a humanpatient, in need of treatment mediated by inhibition of SARS-relatedcoronavirus activity, by any known or suitable method of administeringthe dose, including topically, for example, as an ointment or cream;orally; rectally, for example, as a suppository; parenterally byinjection; intravenously; or continuously by intravaginal, intranasal,intrabronchial, intraaural, or intraocular infusion. When thecomposition is administered in conjunction with a cytotoxic drug, thecomposition can be administered before, with, and/or after introductionof the cytotoxic drug. However, when the composition is administered inconjunction with radiotherapy, the composition is preferably introducedbefore radiotherapy is commenced.

[0450] The phrases “therapeutically effective amount” and “effectiveamount” are intended to mean the amount of an inventive agent that, whenadministered to a mammal in need of treatment, is sufficient to effecttreatment for injury or disease conditions alleviated by the inhibitionof SARS viral replication such as for potentiation of anti-cancertherapies or inhibition of neurotoxicity consequent to stroke, headtrauma, and neurodegenerative diseases. The amount of a givenSARS-inihibiting agent used in the method of the invention that will betherapeutically effective will vary depending upon factors such as theparticular SARS-inihibiting agent, the disease condition and theseverity thereof, the identity and characteristics of the mammal in needthereof, which amount may be routinely determined by artisans.

[0451] It will be appreciated that the actual dosages of theSARS-inhibiting agents used in the pharmaceutical compositions of thisinvention will be selected according to the properties of the particularagent being used, the particular composition formulated, the mode ofadministration and the particular site, and the host and condition beingtreated. Optimal dosages for a given set of conditions can beascertained by those skilled in the art using conventionaldosage-determination tests. For oral administration, e.g., a dose thatmay be employed is from about 0.001 to about 1000 mg/kg body weight,preferably from about 0.1 to about 100 mg/kg body weight, and even morepreferably from about 1 to about 50 mg/kg body weight, with courses oftreatment repeated at appropriate intervals.

[0452] Protein functions required for coronavirus replication andtranscription are encoded by the so-called “replicase” gene. Twooverlapping polyproteins are translated from this gene and extensivelyprocessed by viral proteases. The C-proximal region is processed ateleven conserved interdomain junctions by the coronavirus main or“3C-like” protease. The name “3C-like” protease derives from certainsimilarities between the coronavirus enzyme and the well-knownpicornavirus 3C proteases. These include substrate preferences, use ofcysteine as an active site nucleophile in catalysis, and similarities intheir putative overall polypeptide folds. A comparison of the amino acidsequence of the SARS-associated coronavirus 3C-like protease to that ofother known coronaviruses shows the amino acid sequence to be highlyconserved, particularly in the catalytically important regions of theprotease (FIG. 1).

[0453] Amino acids of the substrate in the protease cleavage site arenumbered from the N to the C terminus as follows: -P3-P2-P1-P1′-P2′-P3′,with cleavage occurring between the P1 and P1′ residues (Schechter &Berger, 1967). Substrate specificity is largely determined by the P2, P1and P1′ positions. Coronavirus main protease cleavage site specificitiesare highly conserved with a requirement for glutamine at P1 and a smallamino acid at P1′ (Journal of General Virology 83, pp. 595-599 (2002)).

[0454] For almost 10 years, Pfizer-La Jolla has been engaged in aneffort to discover and develop drugs with utility for treating thecommon cold by targeting a key enzyme in rhinovirus replication, namelythe 3C protease. Potent, non-toxic agents with broad-spectrum activityagainst multiple rhinovirus serotypes have been identified. Thesecompounds are described, for example, in U.S. Pat. Nos. 6,514,997,6,531,452 and 5,962,487 each of which is incorporated herein in itsentirety by reference. Recentiy, Hilgenfeld and colleagues published ahigh-resolution x-ray structure of the porcine transmissiblegastroenteritis coronavirus main protease (The EMBO Journal, Vol. 21,pp. 3213-3224 (2002)). Atomic coordinates are available through theProtein Data Bank under accession code 1LVO. Our observations of thecatalytic and structural similarities between rhinovirus 3C protease andcoronavirus “3C-like” main protease, lead to the conclusion thatselected inhibitors of rhinovirus 3C protease would be useful againstthe coronavirus main (3C-like) protease (FIG. 3).

[0455] Several considerations come into play when developing strategiesfor design of therapeutically efficacious serine and cysteine proteaseinhibitors. For many of these proteins, specificity pockets forsubstrate (or inhibitor) recognition are shallow, and bindingdeterminants are widely dispersed over large surface areas. Difficultiesinherent in discovering small molecules with high affinity for suchbinding sites are in many respects analogous to those encountered inattempting to disrupt proteinBprotein interactionswith small effectormolecules. Serine proteases such as factor Xa and thrombin, proteinsinvolved in the blood-coagulation pathway with deep well defined S1specificity pockets, have been targeted effectively with structurallydiverse, small, noncovalent inhibitors and thus are exceptions to thisgeneralization (19). However, for virally encoded serine and cysteineproteases of known structure, such as the herpes family of sedneproteases, hepatitis C NS3 protease, picornavirus 3C proteases andcoronaviral 3C-like proteases, the fact that substrate recognition ismodulated by extensive proteinBprotein interactions represents asignificant impediment for design of specific inhibitors.

[0456] Peptidic substrates in which the scissile amide carbonyl isreplaced by a Michael acceptor were first introduced as specificirreversible inhibitors of the cysteine protease papain by Hanzlik andcoworkers (20, 21). We reasoned that, although this reaction is probablyfacilitated by the especially nucleophilic thiolateimidazolium ion pairin papain-like cysteine proteases, suitably activated Michael acceptorsmight also undergo addition by the presumably less nucleophiliccatalytic cysteine of 3C and 3C-like proteases.

[0457] Covalent irreversible inactivation of 3C and 3C-like proteases byMichael acceptors proceeds according to a kinetic mechanism that can bebroken down into two parts.

[0458] The inhibitor initially forms a reversible encounter complex with3C, which can then undergo a chemical step (nucleophilic attack by thereactive site Cys) leading to stable covalent-bond formation. Theobserved second-order rate constant for inactivation (k_(obs)/l) dependson both the equilibrium binding constant k₂/k₁ and the chemical rate forcovalent bond formation k₃ (Meara, J. P. & Rich, D. H. (1995) Bioorg.Med. Chem. Lett. 5, 2277-2282). We anticipated that Michael-acceptorinhibitors with specificity for 3C-like protease, as with 3C protease,would likely achieve high rates of enzyme inactivation by combining goodequilibrium binding with a modest rate of covalent-bond formation. Therate of chemical inactivation presumably depends on not only theintrinsic electrophilic character of the inhibitor, but on how thereactive vinyl group is oriented relative to the Cys in the reactivesite before nucleophilic attack and on the extent to which thetransition state for the reaction can be stabilized by the enzyme.Mechanism-based activation of an inherently weak Michael acceptor as ameans of increasing the rate of the chemical step, and thus k_(obs)/l,is conceptually more attractive than attempting to achieve a similareffect by simply increasing intrinsic electrophilic reactivity, whichwould likely impart undesirable properties to such compounds.

EXAMPLES

[0459] In the examples described below, unless otherwise indicated, alltemperatures are set forth in degrees Celsius and all parts andpercentages are by weight. Reagents may be purchased from commercialsuppliers, such as Sigma-Aldrich Chemical Company, or LancasterSynthesis Ltd. and may be used without further purification unlessotherwise indicated. Tetrahydrofuran (THF) and N,N-dimethylformamide(DMF) may be purchased from Aldrich in Sure Seal bottles and used asreceived. All solvents may be purified using standard methods known tothose skilled in the art, unless otherwise indicated.

[0460] The SARS coronavirus protease inhibitors as used in the method ofthe present invention can be prepared as described in U.S. patentapplication Ser. Nos. 09/301977 and 09/726376 (Dragovich et al.), eachof which is incorporated herein in their entirety by reference.

[0461] Preferred compounds in accordance with the invention may beprepared in manners analogous to those specifically described below.

Example 1

[0462] Protection from Infection

[0463] The ability of compounds to protect cells against infection bythe SARS coronavirus is measured by a cell viability assay similar tothat described in Weislow, O. S., Kiser, R., Fine, D. L., Bader,J.,Shoemaker, R. H., and Boyd, M. R. 1989. New Soluble-Formazan Assay forHIV-1 Cytopathic Effects: Application to High-Flux Screening ofSynthetic and Natural Products for AIDS-Antiviral Activity. Journal ofthe National Cancer Institute 81(08):577-586), utilizing neutral redstaining as an endpoint. Briefly, Vero cells are resuspended in mediumcontaining appropriate concentrations of compound or medium only. Cellsare infected with SARS-associated virus or mock-infected with mediumonly. One to seven days later, neutral red is added to the test platesand following incubation at 37° C. for one hour, cells are solubilizedand the amount of neutral red produced is quantifiedspectrophotometrically at 540 nm. Data is expressed as the percent ofneutral red produced in compound-treated cells compared to neutral redproduced in wells of uninfected, compound-free cells. The fifty percenteffective concentration (EC50) is calculated as the concentration ofcompound that increases the percent of neutral red production ininfected, compound-treated cells to 50% of that produced by uninfected,compound-free cells. The 50% cytotoxicity concentration (CC50) iscalculated as the concentration of compound that decreases thepercentage of neutral red produced in uninfected, compound-treated cellsto 50% of that produced in uninfected, compound-free cells. Thetherapeutic index is calculated by dividing the cytotoxicity (CC50) bythe antiviral activity (EC50).

Example 2

[0464] Viral Yield Assay

[0465] The ability of compounds to protect cells by infection isevaluated in a virus yield assay similar to that described in A. K.Patick, S. L. Binford, M. A. Brothers, R. L. Jackson, C. E. Ford, M. D.Diem, F. Maldonado, P. S. Dragovich, R. Zhou, T. J. Prins, S. A.Fuhrman, J. W. Meador, L. S. Zalman, D. A. Matthews and S. T. Worland.1999. In vitro antiviral activity of AG7088, a potent inhibitor of humanrhinovirus 3C protease. Antimicrob. Agents and Chemo. 43:2444-2450.Briefly, 0.2 ml of serial ten-fold dilutions of SARS-associated virus isallowed to adsorb onto monolayers of Vero cells. After one houradsorption, the cell monolayers are washed twice with PBS and overlayedwith medium containing 0.5% Seaplaque agarose (FMC Bioproducts,Rockland, Me.). After one to seven days of incubation at 34° C., thecell monolayers are fixed with EAF (65% ethanol, 22% acetic acid, and 4%formaldehyde), stained with 1% crystal violet and virus plaquesenumerated. Data is expressed as plaque forming units (PFU) per ml. Thefifty percent EC50 is calculated as the concentration of compound thatdecreases the number of PFU/ml in infected, compound-treated cells to50% of that produced by infected, compound-free cells.

Example 3

[0466] Coronavirus 3C Protease FRET Assay and Analysis

[0467] Proteolytic activity of Coronavirus 3C protease is measured usinga continuous fluorescence resonance energy transfer assay. Thesubstrate, DABCYL-GRAVFQGPVG-EDANS, is prepared by modification of thecore decapeptide (American Peptide Systems) and purified prior to use byHPLC using a C-18 resin (Alltech). Other peptide cores are possible andmay, for example, be derived from protease cleavage sites in thepublished sequence of the SARS coronavirus. Preferred peptides retainthe P1 and P1′ amino acids (QG) of the above decapeptide (theproteolytic cleavage site). In addition, other fluorescentprobe/quencher combinations are possible. The assays include reactionbuffer (50 mM Tris, pH 7.5, 1 mM EDTA 0.1 to 10 □M substrate, 5 to 50 nMcoronavirus 3C protease, 2% DMSO and inhibitor as appropriate. Cleavageof the DABCYL-EDANS substrate peptide is monitored by the appearance offluorescent emission at 490 nm (following excitation at 336 nm). Dataare analyzed with the non-linear regresssion analysis programKalidagraph using the equation:

FU=offset+(limit)(1−e^(−(kobs)t))

[0468] where offset equals the fluorescence signal of the uncleavedpeptide substrate, and limit equals the fluorescence of fully cleavedpeptide substrate. The kobs is the first order rate constant for thisreaction, and in the absence of any inhibitor represents the utilizationof substrate. In an enzyme start reaction which contains an irreversibleinhibitors, and where the calculated limit is less than 20% of thetheoretical maximum limit, the calculated kobs represents the rate ofinactivation of coronavirus 3C protease. The slope (kobs/l) of a plot ofkobs vs. [I] is a measure of the avidity of the inhibitor for an enzyme.For very fast irreversible inhibitors, kobs/l is calculated fromobservations at only one or two [I] rather than as a slope.

Example 4

[0469] Structure-assisted Selection of Michael acceptor-based Inhibitorsof 3C-like Protease Inhibitors

[0470] Homology Modeling

[0471] A homology model for SARS 3C-like protease was created using theatomic coordinates for the recently published coronavirus “3C-like”protease as a template. BLAST was employed to identify the 3C-likeproteinase from the genomic RNA sequence of SARS (AY274119). Minoradjustment to the BLAST output resulted in an alignment with highpercent identity and few gaps (FIG. 1), and this alignment was used tocreate a homology model with the MODELLER package in Insight2000(Sanchez and Sali 2000).

[0472] Twelve residues with high structural conservation (FIG. 2) wereidentified by visual inspection of the rhinovirus 3C (1CQQ) and TGEV3C-like proteinase (1LVO) structures, as well as the SARS 3C-likeproteinase homology model. The structures were superimposed in a commonreference frame by minimizing the root mean square difference (RMSD)between the backbone atoms of these residues, with RMSD<0.6 Angstroms².Inspection of the structures in the common reference frame demonstratesstrong conservation of the side-chain conformations of the catalyticcysteine and histidine residues (FIG. 3).

[0473] Modeling Analysis

[0474] Electronic and steric characteristics of coronavirus “3C-like”protease near the active site cysteine and the adjacent S1 and S1′specificity pockets are similar to those of rhinovirus 3C protease withcorresponding features closely aligned based on the structuralsuperposition described above. In the S1′ specificity pocket, main-chainnitrogens Gly145 and Cys147 activate the carbonyl oxygen in AG7088. Thesequence and structural location of these two residues are conserved inthe TGEV structure (Gly142 and Cys144). In the S1 specificity pocket,there are three hydrogen bonds between AG7088 and rhinovirus 3C protease(FIG. 4). These three hydrogen bonds are preserved in the SARS model,one of them involving a corresponding His Nitrogen in the two proteins,and the others substituted with alternate residues. Despitesubstitutions in the sequence of the S1 pocket, the solvent accessiblesurfaces of rhinovirus 3C protease and the SARS model have considerableagreement in the P1 binding site (FIG. 5). Further examination of thesuperposed structures indicates that an inhibitor such as AG7088 couldall seven of the hydrogen bonds with coronavirus “3C-like” protease atP1, P2, and P3 that are observed for rhinovirus 3C protease (FIG. 4).Differences between the structures are most prevalent in the S3 and S4pockets, suggesting that optimal inhibitors of rhinovirus 3C proteaseand SARS will differ in this region. Furthermore, the S2 specificitypocket is more constrained in the coronavirus protease, suggesting thatinhibitors having side chains smaller than fluorophenyalanine (as inAG7088) could be preferred. This is consistent with the prevalence ofLeu in many of the known coronavirus cleavage site sequences (Hegyi andZiebuhr 2002). Coronavirus main protease cleavage site specificities arehighly conserved with a requirement for glutamine at P1 and a smallamino acid at P1′ (Hegyi and Ziebuhr 2002). Picornavirus 3C proteasesalso favor cleavage sites with glutamine at P1 and either Gly or Ala atP1′. The structural superposition described above indicates that the twoproteins differ considerably in exactly how their respective S4specificity pockets are constructed. The polypeptide chain loops thatform S4 are also positioned differently relative to S1, S2, and S3 inthe two viral proteases.

[0475] The modeling analysis leads to the following suggestions forinhibitors:

[0476] 1. Michael acceptor based inhibitors with appropriate specificityelements should covalently inactivate coronavirus “3C-like” proteasewith both methyl and ethyl ester containing compounds.

[0477] 2. Compounds with glutamine or the lactam side chain at P1 shouldbe chosen.

[0478] 3. Compounds with differing substituents at P2 should be selectedincluding phe but also smaller side chains such as leu and val.

[0479] 4. Wide variability should be acceptable at P3 as this side chainsite is fully solvent accessible.

[0480] 5. Size and conformational flexibility at P4 may be important.Smaller is probably better than larger based on modeling. Includethiocarbamate containing analogs.

[0481] Michael acceptor containing SARS protease inhibitor compounds areselected based on the above qualitative criteria. Alternatively, one mayalso dock available compounds to a homology model of the SARS protease.Such a model could be constructed using the known structure of porcinecoronavirus protease and the gene sequence of the SARS virus “3C-like”protease.

Example 5

[0482] Michael acceptor-based Inhibitors of the SARS Protease

[0483] Michael acceptor-based inhibitors having the criteria discussedabove are assayed using the protease and antiviral assays describedabove in Examples 1-3. The following compounds are identified asinhibitors of the 3C-like protease of the SARS-associated virus.

[0484] Table 1 below provides examples of inhibitor compounds that areuseful as SARS-related 3C protease inhibitors. However, the invention isnot limited to these particular examples. TABLE 1 No. MOL STRUCTURE CHEMNAME MOL FORMULA MOL Wt 1

4-[2-(3-acetylamino-2-oxo-2H-pyridin- 1-yl)-3-phenypropionylamino]-6-carbamoylhex-2-enoic acid ethyl ester C25 H30 N4 O6 482.534 2

6-carbamoyl-4-{□2-[3-(2,2- dimethylpropionylamino)-2-oxo-2H-pyridin-1-yl]-3-phenylpropionylamino}- hex-2-enoic acid ethyl ester C28H36 N4 O6 524.614 3

4-[2-(3-benzyloxycarbonylamino-4- methyl-2-oxo-2H-pyridin-1-yl)-3-phenylpropionylamino-6- carbamoylhex-2-enoic acid ethyl ester C32 H36 N4O7 588.657 4

4-[2-(3-Benzyloxycarbonylamino-2- oxo-2H-pyridin-1-yl)-3-cyclohexyl-propionylamino]-6-carbamoyl-hex-2- enoic acid ethyl ester C31 H40 N4 O7580.678 5

6-Carbamoyl-4-(2-{4-methyl-3-[(5- methyl-isoxazole-3-carbonyl)-amino]-2-oxo-2H-pyridin-1-yl}-3-phenyl- propionylamino)-hex-2-enoic acid ethylester C29 H33 N5 O7 563.608 6

4-[2-(3-benzyloxycarbonylamino-2-oxo- 2H-pyridin-1-yl)-3-phenylpropionylamino]-5-(2- oxopyrrolidin-3-yl)-pent-2-enoic acid ethylester C33 H36 N4 O7 600.668 7

4-(3-(4-fluorophenyl)-2-{3-[(5- methylisoxazole-3-carbonyl)-amino]-2-oxo-2H-pyridin-1-yl}-propionylamino)-5-(2-oxopyrrolidin-3-yl)-pent-2-enoic acid ethyl ester C30 H32 F N5 O7593.609 8

4-(2-{3-[(5-methylisoxazole-3- carbonyl)-amino]-2-oxo-2H-pyridin-1-yl}-butyrylamino)-5-(2-oxopyrrolidin-3- yl)-pent-2-enoic acid ethylester C25 H31 N5 O7 513.548 9

4-(2-{3-[(5-Methyl-isoxazole-3- carbonyl)-amino]-2-oxo-2H-pyridin-1-yl}-pent-4-ynoylamino)-5-(2-oxo- pyrrolidin-3-yl)-pent-2-enoic acid 2,2-dimethyl-propyl ester C29 H35 N5 O7 565.623 10

(E)-(S)-4-[(S)-3-(3,4-Difluoro-phenyl)-2-(3-{[1-(5-methyl-isoxazol-3-yl)- methanoyl]-amino}-2-oxo-2H-pyridin-1-yl)-propanoylamino]-5-(2-oxo- pyrrolidin-3-yl)-pent-2-enoic acid ethylester C30 H31 F2 N5 O7 611.599 11

(E)-(S)-4-[(S)-2-(3-{[1-(5-Methyl- isoxazol-3-yl)-methanoyl]-amino}-2-oxo-2H-pyridin-1-yl)-butanoylamino]-5-((S)-2-oxopyrrolidin-3-yl)-pent-2-enoic acid 2,2-dimethyl-propyl esterC28 H37 N5 O7 555.628 12

(E)-(S)-2-methyl-4-[(S)-2-(3-{[1-(5- methylisoxazol-3-yl)-methanoyl]-amino}-2-oxo-2H-pyridin-1-yl)-pent-4-ynoylamino]-5-((S)-2-oxopyrrolidin-3- yl)-pent-2-enoic acid ethyl esterC27 H31 N5 O7 537.57 13

(E)-(S)-4-[(S)-2-(3-{[1-(5-Methyl- isoxazol-3-yl)-methanoyl]-amino}-2-oxo-2H-pyridin-1-yl)-pent-4- ynoylamino]-5-((S)-2-oxo-pyrrolidin-3-yl)-pent-2-enoic acid isopropyl ester C27 H31 N5 O7 537.57 14

(E)-(S)-4-[(S)-3-(3,4-Difluorophenyl)-2- (3-{[1-(5-methylisoxazol-3-yl)-methanoyl]-amino}-2-oxo-2H-pyridin-1- yl)-propanoylamino]-5-((S)-2-oxopyrrolidin-3-yl)-pent-2-enoic acid isopropyl ester C31 H33 F2 N5 O7625.626 15

(E)-(S)-4-[(S)-3-(3,4-Difluorophenyl)-2- (3-{[1-(5-methylisoxazol-3-yl)-methanoyl]-amino}-2-oxo-2H-pyridin-1- yl)-propanoylamino]-5-((S)-2-oxopyrrolidin-3-yl)-pent-2-enoic acid cyclopentyl ester C33 H35 F2 N5 O7651.664 16

(E)-(S)-4-[(S)-3-(3,4-Difluorophenyl)-2- (3-{[1-(5-methylisoxazol-3-yl)-methanoyl]-amino}-2-oxo-2H-pyridin-1- yl)-propanoylamino]-5-((S)-2-oxopyrrolidin-3-yl)-pent-2-enoic acid cyclohexyl ester C34 H37 F2 N5 O7665.69 17

(E)-4-[2-(3-{[1-(5-Methyl-isoxazol-3-yl)-methanoyl]-amino}-2-oxo-2H-pyridin-1- yl)-pent-4-ynoylamino]-5-(2-oxo-pyrrolidin-3-yl)-pent-2-enoic acid cyclohexyl ester C30 H35 N5 O7577.635 18

(E)-4-[2-(3-{[1-(5-Methyl-isoxazol-3-yl)-methanoyl]-amino}-2-oxo-2H-pyridin-1-yl)-butanoylamino]-5-(2-oxo-pyrrolidin- 3-yl)-pent-2-enoic acidcyclohexyl ester C29 H37 N5 O7 567.639 19

(E)-4-[2-(3-{[1-(5-Methyl-isoxazol-3-yl)-methanoyl]-amino}-2-oxo-2H-pyridin-1-yl)-butanoylamino]-5-(2-oxo-pyrrolidin- 3-yl)-pent-2-enoic acid benzylester C30 H33 N5 O7 575.619 20

(E)-(S)-4-[(S)-2-(3-{[1-(5-Methyl- isoxazol-3-yl)-methanoyl]-amino}-2-oxo-2H-pyridin-1-yl)-3-phenyl- propanoylamino]-5-((S)-2-oxo-pyrrolidin-3-yl)-pent-2-enoic acid isopropyl ester C31 H35 N5 O7 589.64621

6-Carbamoyl-4-{3-(4-chloro-phenyl)-2- [(4-methoxy-1H-indole-2-carbonyl)-amino]-propionylamino}-hex-2-enoic acid ethyl ester C28 H31 Cl N4 O6555.028 22

6-Carbamoyl-4-{3-(4-fluoro-phenyl)-2- [(4-methoxy-1H-indole-2-carbonyl)-amino]-propionylamino}-hex-2-enoic acid ethyl ester C28 H31 F N4 O6538.573 23

6-Carbamoyl-4-{3-(3-fluoro-phenyl)-2- [(4-methoxy-1H-indole-2-carbonyl)-amino]-propionylamino}-hex-2-enoic acid ethyl ester C28 H31 F N4 O6538.573 24

(E)-(S)-4-[(1-Naphthalen-2-yl- methanoyl)-amino]-5-((S)-2-oxo-pyrrolidin-3-yl)-pent-2-enoic acid ethyl ester C22 H24 N2 O4 380.442 25

4-[2-(3-benzyloxycarbonylamino-2-oxo- 2H-pyridin-1-yl)-3-phenylpropionylamino]-6- carbamoylhex-2-enoic acid ethyl ester C31 H34N4 O7 574.631 26

4-{2-(4-fluorobenzyl)-6-methyl-5-[(5-methylisoxazole-3-carbonyl)-amino]-4-oxoheptanoylamino}-5-(2-oxopyrrolidin- 3-yl)-pent-2-enoic acid ethylester C31 H39 F N4 O7 598.668

[0485] While the invention has been described in terms of variouspreferred embodiments and specific examples, the invention should beunderstood as not being limited by the foregoing detailed description,but as being defined by the appended claims and their equivalents.

What is claimed is:
 1. A method of interfering with or preventing SARSrelated coronavirus viral replication activity comprising contacting aSARS related coronavirus protease with a therapeutically effectiveamount of a rhinovirus 3C protease inhibitor.
 2. A method according toclaim 1, wherein said inhibitor is administered orally, intravenously orby inhalation.
 3. A pharmaceutical composition for the treatment of SARSrelated cornoavirus in a mammal comprising an amount of a rhinovirusinhibitor that is effective in treating SARS related coronavirus and apharmaceutically acceptable carrier.
 4. A method according to claim 1utilizing an inhibitor of formula l:

wherein M is O or S; R₁ is H, F, an alkyl group, OH, SH, or an O-alkylgroup; R₂ and R₅ are independently selected from H,

or an alkyl group, wherein said alkyl group is different from

with the proviso that at least one of R₂ or R₅ must be

and wherein, when R₂ or R₅ is

X is ═CH or ═CF and Y, is ═CH or ═CF, or X and Y₁ together with Q′ forma three-membered ring in which Q′ is —C(R₁₀)(R₁₁)— or —O—, X is —CH— or—CF—, and Y₁ is —CH—, —CF—, or —C(alkyl)—, where R₁₀ and R₁₁independently are H, a halogen, or an alkyl group, or, together with thecarbon atom to which they are attached, form a cycloalkyl group or aheterocycloalkyl group, or X is —CH₂—, —CF₂—, —CHF—, or —S—, and Y₁ is—O—, —S—, —NR₁₂—, —C(R₁₃)(R₁₄)—, —C(O)—, —C(S)—, or —C(CR₁₃R₁₄)—,wherein R₁₂ is H or alkyl, and R₁₃ and R₁₄ independently are H, F, or analkyl group, or, together with the atoms to which they are bonded, forma cycloalkyl group or a heterocycloalkyl group; A₁ is C, CH, CF, S, P,Se, N, NR₁₅, S(O), Se(O), P—OR₁₅, or P—NR₁₅R₁₆, wherein R₁₅ and R₁₆independently are an alkyl group, a cycloalkyl group, a heterocycloalkylgroup, an aryl group, or a heteroaryl group, or, together with the atomto which they are bonded, form a heterocycloalkyl group; D₁ is a moietywith a lone pair of electrons capable of forming a hydrogen bond; and B₁is H, F, an alkyl group, a cycloalkyl group, a heterocycloalkyl group,an aryl group, a heteroaryl group, —OR₁₇, —SR₁₇, —NR₁₇R₁₈, —NR₁₉NR₁₇R₁₈,or —NR₁₇OR₁₈, wherein R₁₇, R₁₈, and R₁₉ independently are H, an alkylgroup, a cycloalkyl group, a heterocycloalkyl group, an aryl group, aheteroaryl group, or an acyl group; and with the provisos that when D₁is the moiety □N with a lone pair of electrons capable of forming ahydrogen bond, B₁ does not exist; and when A₁ is an sp³ carbon, B₁ isnot —NR₁₇R₁₈ when D₁ is the moiety —NR₂₅R₂₆ with a lone pair ofelectrons capable of forming a hydrogen bond, wherein R₂₅ and R₂₆ areindependently H, an alkyl group, a cycloalkyl group, a heterocycloalkylgroup, an aryl group, or a heteroaryl group; and wherein D₁-A₁-B₁optionally forms a nitro group where A₁ is N; and further wherein, whenR₂ or R₅ is

X is ═CH or ═CF and Y₂ is ═C, ═CH, or ═CF, or X and Y₂ together with Q′form a three-membered ring in which Q′ is —C(R₁₀)(R₁₁)— or —O—, X is—CH— or —CF—, and Y₂ is —CH—, —CF—, or —C(alkyl)—, where R₁₀ and R₁₁independently are H, a halogen, or an alkyl group, or, together with thecarbon atom to which they are attached, form a cycloalkyl group or aheterocycloalkyl group, or X is —CH₂—, —CF₂—, —CHF—, or —S—, and Y₂ is—O—, —S—, —N(R′₁₂)—, —C(O)—, —C(R′₁₃)(R′₁₄)—, —C(S)—, or —C(CR′₁₃R′₁₄)—,wherein R′₁₂ is H, an alkyl group, a cycloalkyl group, aheterocycloalkyl group, an aryl group, a heteroaryl group, —OR′₁₃,—NR′₁₃R′₁₄, —C(O)—R′₁₃, —SO₂R′₁₃, or —C(S)R′₁₃, and R′₁₃ and R′₁₄,independently are H, F, or an alkyl group, a cycloalkyl group, aheterocycloalkyl group, an aryl group, or a heteroaryl group, or,together with the atom to which they are attached, form a cycloalkylgroup or a heterocycloalkyl group; A₂ is C, CH, CF, S, P, Se, N, NR₁₅,S(O), Se(O), P—OR₁₅, or P—NR₁₅R₁₆, wherein R₁₅ and R₁₆ independently arean alkyl group, a cycloalkyl group, a heterocycloalkyl group, an arylgroup, or a heteroaryl group, or, together with the atom to which theyare bonded, form a heterocycloalkyl group; D₂ is a moiety with a lonepair of electrons capable of forming a hydrogen bond; and B₂ is H, F, analkyl group, a cycloalkyl group, a heterocycloalkyl group, an arylgroup, a heteroaryl group, —OR₁₇, —SR₁₇, —NR₁₇R₁₈, —NR₁₉NR₁₇R₁₈, or—NR₁₇OR₁₈, wherein R₁₇, R₁₈, and R₁₉ independently are H, an alkylgroup, a cycloalkyl group, a heterocycloalkyl group, an aryl group, aheteroaryl group, or an acyl group; and further wherein any combinationof Y₂, A₂, B₂, and D₂ optionally can form a cycloalkyl group, aheterocycloalkyl group, an aryl group, or a heteroaryl group; R₃ and R₆are independently H, F, an alkyl group, a cycloalkyl group, aheterocycloalkyl group, an aryl group, a heteroaryl group, —C(O)R₁₇,—OR₁₇, —SR₁₇, —NR₁₇R₁₈, —NR₁₉NR₁₇R₁₈, or —NR₁₇OR₁₈, wherein R₁₇, R₁₈,and R₁₉ independently are H, an alkyl group, a cycloalkyl group, aheterocycloalkyl group, an aryl group, a heteroaryl group, or an acylgroup; or, R₃ and R₆, together with the carbon atom to which they areattached, form a cycloalkyl group or a heterocycloalkyl group; R₇ is H,an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an arylgroup, a heteroaryl group, —OR₁₇, —SR₁₇, —NR₁₇R₁₈, —NR₁₉NR₁₇R₁₈, or—NR₁₇OR₁₈, wherein R₁₇, R₁₈, and R₁₉ independently are H, an alkylgroup, a cycloalkyl group, a heterocycloalkyl group, an aryl group, aheteroaryl group, or an acyl group; or R₇, together with R₃ or R₆ andthe atoms to which they are attached, forms a heterocycloalkyl group;R₂₀ is H, OH, or any suitable organic moiety; and Z and Z₁ areindependently H, F, an alkyl group, a cycloalkyl group, aheterocycloalkyl group, an aryl group, a heteroaryl group, —C(O)R₂₁,—CO₂R₂₁, —CN, —C(O)NR₂₁,R₂₂, —C(O)NR₂₁OR₂₂, —C(S)R₂₁, —C(S)NR₂₁R₂₂,—NO₂, —SOR₂₁, —SO₂R₂₁, —SO₂NR₂₁R₂₂, —SO(NR₂₁)(OR₂₂), —SONR₂₁, —SO₃R₂₁,—PO(OR₂₁)₂, —PO(R₂₁)(R₂₂), —PO(NR₂₁R₂₂)(OR₂₃), PO(NR₂₁R₂₂)(NR₂₃R₂₄),—C(O)NR₂₁NR₂₂R₂₃, or —C(S)NR₂₁NR₂₂R₂₃, wherein R₂₁, R₂₂, R₂₃, and R₂₄are independently H, an alkyl group, a cycloalkyl group, aheterocycloalkyl group, an aryl group, a heteroaryl group, an acylgroup, or a thioacyl group, or wherein any two of R₂₁, R₂₂, R₂₃, andR₂₄, together with the atom(s) to which they are bonded, form aheterocycloalkyl group; or Z₁, as defined above, together with R₁, asdefined above, and the atoms to which Z₁ and R₁ are bonded, form acycloalkyl or heterocycloalkyl group, or Z and Z₁, both as definedabove, together with the atoms to which they are bonded, form acycloalkyl or heterocycloalkyl group; or a pharmaceutically acceptableprodrug, salt, active metabolite, or solvate thereof; and wherein saidcompound, or pharmaceutically acceptable prodrug, salt, activemetabolite, or solvate thereof, has antipicornaviral activity with anEC₅₀ less than or equal to 10 μM in a HI-HeLa cell culture assay.
 5. Amethod according to claim 1 utilizing a rhinovirus inhibitor of theformula II:

wherein R₁ is:

or a pharmaceutically acceptable salt, solvate, prodrug, orpharmaceutically active metabolite thereof.
 6. A method according toclaim 1 utilizing a rhinovirus inhibitor of the formula IIB:

wherein: R₁₀ is H or CH₃; R₂₀ is H, OH, CH₂OH, or OCH₂Ph; R₃₀ is H, OH,or OCH₂Ph; R₄₀ is H or CN; and R₅₀ is CH₂CH₃, CH₃, CH₂Ph, CH₂CH₂Ph,CH₂CH₂OH, or CH₂(2-pyridyl); or a pharmaceutically acceptable salt,solvate, prodrug, or pharmaceutically active metabolite thereof.
 7. Amethod according to claim 1 utilizing a rhinovirus inhibitor of theformula IIC:

wherein R₁₀₀ is CH₃, phenyl, Ph(4-NCH₃), Ph(4-OCH₃), 2-pyridyl, or2-furyl; or a pharmaceutically acceptable salt, solvate, prodrug, orpharmaceutically active metabolite thereof.
 8. A method according toclaim 1 utilizing a rhinovirus inhibitor of the formula III:

wherein: R^(a1) is a cycloalkyl, heterocycloalkyl, aryl or heteroarylgroup, provided that R^(a1) is not a substituted pyrrolidinyl, where thecycloalkyl, heterocycloalkyl, aryl or heteroaryl group is unsubstitutedor substituted with one or more suitable substituents; R^(c) is asubstituent having the formula:

wherein: R^(f) and R^(g) are each independently H or lower alkyl; m is 0or 1; p is an integer of from 0 to 5; A₁ is CH or N; when p is 1, 2, 3,4, or 5, A₂ is C(R^(h))(R^(i)), N(R^(j)), S, S(O), S(O)₂, or O, and whenp is 0, A₂ is C(R^(h))(R^(i))(R^(j)), N(R^(i))(R^(j)), S(R^(i)),S(O)(R^(i)), S(O)₂(R^(i)), or O(R^(i)), where each R^(h), R^(i) andR^(j) is independently H or a lower alkyl group; each A₃ present isindependently C(R^(h))(R^(i)), N(R^(j)), S, S(O), S(O)₂, or O; whereeach R^(h), R^(i) and R^(j) is independently H or lower alkyl; when p is1, 2, 3, 4, or 5, A₄ is N(R^(k)), C(R^(h))(R^(i)), or O; and when p is0, A₄ is N(R^(k))(R^(i)), C(R^(h))(R^(i))(R^(j)), and O(R^(i)), whereeach R^(h), R^(i) and R^(j) is independently H or lower alkyl, eachR^(k) is H, alkyl, aryl, or acyl, and each R^(l) is H, alkyl, or aryl;provided that no more than two heteroatoms occur consecutively in theabove-depicted ring formed by A₁, (A₂)_(m), (A₃)_(p), A₄, and C═O, whereeach dotted line in the ring depicts a single bond when A₂ is presentand a hydrogen atom when A₂ is absent; R^(d) is H, halogen, hydroxyl oran alkyl, alkoxy or alkylthio group, where the alkyl, alkoxy oralkylthio group is unsubstituted or substituted with one or moresuitable substituents; R^(b) is H or an alkyl group, unsubstituted orsubstituted with one or more suitable substituents; Z and Z¹ are eachindependently H, F, an alkyl, cycloalkyl, heterocycloalkyl, aryl orheteroaryl group, where the alkyl, cycloalkyl, heterocycloalkyl, aryl orheteroaryl group is unsubstituted or substituted with one or moresuitable substituents, —C(O)R^(n) —CO₂R^(n) —CN, —C(O)NR^(n)R^(o),—C(O)NR^(n)OR^(o), —C(S)R^(n), —C(S)OR^(n) —C(S)NR^(n)R^(o),—C(═NR^(n))R^(o), —C(═NR^(n))OR^(o), —NO₂, —SOR^(o), —SO₂R^(n),—SO₂NR^(n)R^(o), —SO₂(NR^(n))(OR^(o)), —SONR^(n), —SO₃R^(n),—PO(OR^(n))₂, —PO(OR^(n))(OR^(o)), —PO(NR^(n)R^(o))(OR^(p)),—PO(NR^(n)R^(o))(NR^(p)R^(q)), —C(O)NR^(n)NR^(o)R^(p),—C(S)NR^(n)NR^(o)R^(p), where R^(n), R^(o), R^(p) and R^(q) are eachindependently H or an alkyl, cycloalkyl, aryl, heterocycloalkyl, acyl orthioacyl group, where the alkyl, cycloalkyl, aryl, heterocycloalkyl,acyl or thioacyl group is unsubstituted or substituted with one or moresuitable substituents, or where any two of the R^(n), R^(o), R^(p) andR^(q), taken together with the atoms to which they are bonded, form aheterocycloalkyl group, which may be optionally substituted, or Z andR^(d),together with the atoms to which they are bonded, form acycloalkyl or heterocycloalkyl group, where Z and R^(d) are as definedabove except for moieties that cannot form the cycloalkyl orheterocycloalkyl group, or Z and Z¹, together with the atoms to whichthey are bonded, form a cycloalkyl or heterocycloalkyl group, where Zand Z¹ are as defined above (except for moieties that cannot form thecycloalkyl or heterocycloalkyl group); or a prodrug, pharmaceuticallyacceptable salt, pharmaceutically active metabolite, or pharmaceuticallyacceptable solvate thereof.
 9. A method according to claim 1 utilizing arhinovirus inhibitor of the formula IIIA:

wherein: R^(a2) is an alkyl, aryl or heteroaryl group, where the alkyl,aryl or heteroaryl group is unsubstituted or substituted with one ormore suitable substituents; and R^(c) is a substituent having theformula:

wherein: R^(f) and R^(g) are each independently H or lower alkyl; m is 0or 1; p is an integer of from 0 to 5; A₁ is CH or N; when p is 1, 2, 3,4, or 5, A₂ is C(R^(h))(R^(i)), N(R^(j)), S, S(O), S(O)₂, or O, and whenp is 0, A₂ is C(R^(h))(R^(i))(R^(j)), N(R^(i))(R^(j)), S(R^(i)),S(O)(R^(i)), S(O)₂(R^(i)), or O(R^(i)), where each R^(h), R^(i) andR^(j) is independently H or a lower alkyl group; each A₃ present isindependently C(R^(h))(R^(i)), N(R^(j)), S, S(O), S(O)₂, or O; whereeach R^(h), R^(i) and R^(j) is independently H or lower alkyl; when p is1, 2, 3, 4, or 5, A₄ is N(R^(k)), C(R^(h))(R^(i)), or O; and when p is0, A₄ is N(R^(k))(R^(i)), C(R^(h))(R^(i))(R^(j)), and O(R^(i)), whereeach R^(h), R^(i) and R^(j) is independently H or lower alkyl, eachR^(k) is H, alkyl, aryl, or acyl, and each R^(l) is H, alkyl, or aryl;provided that no more than two heteroatoms occur consecutively in theabove-depicted ring formed by A₁, (A₂)_(m), (A₃)_(p), A₄, and C═O, whereeach dotted line in the ring depicts a single bond when A₂ is presentand a hydrogen atom when A₂ is absent; R^(d) is H, halogen, hydroxyl oran alkyl, alkoxy or alkylthio group, where the alkyl, alkoxy oralkylthio group is unsubstituted or substituted with one or moresuitable substituents; R^(b) is H or an alkyl group, unsubstituted orsubstituted with one or more suitable substituents; Z and Z¹ are eachindependently H, F, an alkyl, cycloalkyl, heterocycloalkyl, aryl orheteroaryl group, where the alkyl, cycloalkyl, heterocycloalkyl, aryl orheteroaryl group is unsubstituted or substituted with one or moresuitable substituents, —C(O)R^(n) —CO₂R^(n) —CN, —C(O)NR^(n)R^(o),—C(O)NR OR^(o), —C(S)R^(n), —C(S)OR^(n) —C(S)NR^(n)R^(o),—C(═NR^(n))R^(o), —C(═NR^(n))OR^(o), —NO₂, —SOR^(o), —SO₂R^(n),—SO₂NR^(n)R^(o), —SO₂(NR^(n))(OR^(o)), —SONR^(n), —SO₃R^(n),—PO(OR^(n))₂, —PO(OR^(n))(OR^(o)), —PO(NR^(n)R^(o))(OR^(p)),—PO(NR^(n)R^(o))(NR^(p)R^(q)), —C(O)NR^(n)NR^(o)R^(p),—C(S)NR^(n)NR^(o)R^(p), where R^(n), R^(o), R^(p) and R^(q) are eachindependently H or an alkyl, cycloalkyl, aryl, heterocycloalkyl, acyl orthioacyl group, where the alkyl, cycloalkyl, aryl, heterocycloalkyl,acyl or thioacyl group is unsubstituted or substituted with one or moresuitable substituents, or where any two of the R^(n), R^(o), R^(p) andR^(q), taken together with the atoms to which they are bonded, form aheterocycloalkyl group, which may be optionally substituted, or Z andR^(d), together with the atoms to which they are bonded, form acycloalkyl or heterocycloalkyl group, where Z and R^(d) are as definedabove except for moieties that cannot form the cycloalkyl orheterocycloalkyl group, or Z and Z¹, together with the atoms to whichthey are bonded, form a cycloalkyl or heterocycloalkyl group, where Zand Z¹ are as defined above (except for moieties that cannot form thecycloalkyl or heterocycloalkyl group); or a prodrug, pharmaceuticallyacceptable salt, pharmaceutically active metabolite, or pharmaceuticallyacceptable solvate thereof.
 10. A method according to claim 1 utilizinga rhinovirus inhibitor of the formula IIIB:

wherein: R^(a3) is an aryl, heterocycloalkyl, heteroaryl orarylaminocarbonyl group, where the aryl, heterocycloalkyl, heteroaryl orarylaminocarbonyl group is unsubstituted or substituted with one or moresuitable substituents; and R^(c) is a substituent having the formula:

wherein: R^(f) and R^(g) are each independently H or lower alkyl; m is 0or 1; p is an integer of from 0 to 5; A₁ is CH or N; when p is 1, 2, 3,4, or 5, A₂ is C(R^(h))(R^(i)), N(R^(j)), S, S(O), S(O)₂, or O, and whenp is 0, A₂ is C(R^(h))(R^(i))(R^(j)), N(R^(i))(R^(i)), S(R^(i)),S(O)(R^(i)), S(O)₂(R^(i)), or O(R^(i)), where each R^(h), R^(i) andR^(j) is independently H or a lower alkyl group; each A₃ present isindependently C(R^(h))(R^(i)), N(R^(j)), S, S(O), S(O)₂, or O; whereeach R^(h), R^(i) and R^(j) is independently H or lower alkyl; when p is1, 2, 3, 4, or 5, A₄ is N(R^(k)), C(R^(h))(R^(i)), or O; and when p isO, A₄ is N(R^(k))(R^(i)), C(R^(h))(R^(i))(R^(j)), and O(R^(i)), whereeach R^(h), R^(i) and R^(j) is independently H or lower alkyl, eachR^(k) is H, alkyl, aryl, or acyl, and each R^(l) is H, alkyl, or aryl;provided that no more than two heteroatoms occur consecutively in theabove-depicted ring formed by A₁, (A₂)_(m), (A₃)_(p), A₄, and C═O, whereeach dotted line in the ring depicts a single bond when A₂ is presentand a hydrogen atom when A₂ is absent; R^(d) is H, halogen, hydroxyl oran alkyl, alkoxy or alkylthio group, where the alkyl, alkoxy oralkylthio group is unsubstituted or substituted with one or moresuitable substituents; R^(b) is H or an alkyl group, unsubstituted orsubstituted with one or more suitable substituents; R^(e) is H, halogen,hydroxyl or an alkyl, alkoxy or alkylthio group, where the alkyl, alkoxyor alkylthio group is unsubstituted or substituted with one or moresuitable substituents; Z and Z¹ are each independently H, F, an alkyl,cycloalkyl, heterocycloalkyl, aryl or heteroaryl group, where the alkyl,cycloalkyl, heterocycloalkyl, aryl or heteroaryl group is unsubstitutedor substituted with one or more suitable substituents, —C(O)R^(n)—CO₂R^(n) —CN, —C(O)NR^(n)R^(o), —C(O)NR^(n)OR^(o), —C(S)R^(n),—C(S)OR^(n) —C(S)NR^(n)R^(o), —C(═NR^(n))R^(o), —C(═NR^(n))OR^(o), —NO₂,—SOR^(o), —SO₂R^(n), —SO₂NR^(n)R^(o), —SO₂(NR^(n))(OR^(o)), —SONR^(n),—SO₃R^(n), —PO(OR^(n))₂, —PO(OR^(n))(OR^(o)), —PO(NR^(n)R^(o))(OR^(o)),—PO(NR^(n)R^(o))(NR^(p)R^(o)) —C(O)NR^(n)NR^(o)R^(p),—C(S)NR^(n)NR^(o)R^(p), where R^(n), R^(o), R^(p) and R^(q) are eachindependently H or an alkyl, cycloalkyl, aryl, heterocycloalkyl, acyl orthioacyl group, where the alkyl, cycloalkyl, aryl, heterocycloalkyl,acyl or thioacyl group is unsubstituted or substituted with one or moresuitable substituents, or where any two of the R^(n), R^(o), R^(p) andR^(q), taken together with the atoms to which they are bonded, form aheterocycloalkyl group, which may be optionally substituted, or Z andR^(d),together with the atoms to which they are bonded, form acycloalkyl or heterocycloalkyl group, where Z and R^(d) are as definedabove except for moieties that cannot form the cycloalkyl orheterocycloalkyl group, or Z and Z¹, together with the atoms to whichthey are bonded, form a cycloalkyl or heterocycloalkyl group, where Zand Z¹ are as defined above (except for moieties that cannot form thecycloalkyl or heterocycloalkyl group); or a prodrug, pharmaceuticallyacceptable salt, pharmaceutically active metabolite, or pharmaceuticallyacceptable solvate thereof.
 11. A method according to claim 1 utilizinga rhinovirus inhibitor of the formula IIIC:

wherein: R^(a4) is an aryloxy, heteroaryloxy, alkyloxy, cycloalkyloxy,heterocycloalkyloxy, aryl, cycloalkyl, or heteroaryl group, where thearyloxy, heteroaryloxy, alkyloxy, cycloalkyloxy, heterocycloalkyloxy,aryl, cycloalkyl, or heteroaryl group is unsubstituted or substitutedwith one or more suitable substituents; and R^(c) is a substituenthaving the formula:

wherein: R^(f) and R^(g) are each independently H or lower alkyl; m is 0or 1; p is an integer of from 0 to 5; A₁ is CH or N; when p is 1, 2, 3,4, or 5, A₂ is C(R^(h))(R^(i)), N(R^(j)), S, S(O), S(O)₂, or O, and whenp is 0, A₂ is C(R^(h))(R^(i))(R^(j)), N(R^(i))(R^(j)), S(R^(i)),S(O)(RI), S(O)₂(R^(i)), or O(R^(i)), where each R^(h), R^(i) and R^(j)is independently H or a lower alkyl group; each A₃ present isindependently C(R^(h))(R^(i)), N(R^(i)), S, S(O), S(O)₂, or O; whereeach R^(h), R and R¹ is independently H or lower alkyl; when p is 1, 2,3, 4, or 5, A₄ is N(R^(k)), C(R^(h))(R^(i)), or O; and when p is 0, A₄is N(R^(k))(R^(i)), C(R^(h))(R^(i))(R^(j)), and O(R^(i)), where eachR^(h), R^(i) and R^(j) is independently H or lower alkyl, each R^(k) isH, alkyl, aryl, or acyl, and each R^(l) is H, alkyl, or aryl; providedthat no more than two heteroatoms occur consecutively in theabove-depicted ring formed by A₁, (A₂)_(m), (A₃)_(p), A₄, and C═O, whereeach dotted line in the ring depicts a single bond when A₂ is presentand a hydrogen atom when A₂ is absent; R^(d) is H, halogen, hydroxyl oran alkyl, alkoxy or alkylthio group, where the alkyl, alkoxy oralkylthio group is unsubstituted or substituted with one or moresuitable substituents; R^(b) is H or an alkyl group, unsubstituted orsubstituted with one or more suitable substituents; R^(e) is H, halogen,hydroxyl or an alkyl, alkoxy or alkylthio group, where the alkyl, alkoxyor alkylthio group is unsubstituted or substituted with one or moresuitable substituents; Z and Z¹ are each independently H, F, an alkyl,cycloalkyl, heterocycloalkyl, aryl or heteroaryl group, where the alkyl,cycloalkyl, heterocycloalkyl, aryl or heteroaryl group is unsubstitutedor substituted with one or more suitable substituents, —C(O)R^(n)—CO₂R^(n) —CN, —C(O)NR^(n)R^(o), —C(O)NR^(n)OR^(o), —C(S)R^(n),—C(S)OR^(n) —C(S)NR^(n)R^(o), —C(═NR^(n))R^(o), —C(═NR^(n))OR^(o), —NO₂,—SOR^(o), —SO₂R^(n), —SO₂NR^(n)R^(o), —SO₂(NR^(n))(OR^(o)), —SONR^(n),—SO₃R^(n), —PO(OR^(n))₂, —PO(OR^(n))(OR^(o)), —PO(NR^(n)R^(o))(OR^(p),—PO(NR^(n)R^(o))(NR^(p)R^(q)), —C(O)NR^(n)NR^(o)R^(p),—C(S)NR^(n)NR^(o)R^(p), where R^(n), R°, R^(p) and R^(q) are eachindependently H or an alkyl, cycloalkyl, aryl, heterocycloalkyl, acyl orthioacyl group, where the alkyl, cycloalkyl, aryl, heterocycloalkyl,acyl or thioacyl group is unsubstituted or substituted with one or moresuitable substituents, or where any two of the R^(n), R^(o), R^(p) andR^(q) taken together with the atoms to which they are bonded, form aheterocycloalkyl group, which may be optionally substituted, or Z andR^(d), together with the atoms to which they are bonded, form acycloalkyl or heterocycloalkyl group, where Z and R^(d) are as definedabove except for moieties that cannot form the cycloalkyl orheterocycloalkyl group, or Z and Z¹, together with the atoms to whichthey are bonded, form a cycloalkyl or heterocycloalkyl group, where Zand Z¹ are as defined above (except for moieties that cannot form thecycloalkyl or heterocycloalkyl group); or a prodrug, pharmaceuticallyacceptable salt, pharmaceutically active metabolite, or pharmaceuticallyacceptable solvate thereof.
 12. A method according to claim 1 utilizinga rhinovirus inhibitor of the formula IV:

wherein: Y is —N(R_(y))—, —C(R_(y))(R_(y))—, or —O—, where each R_(y) isindependently H or lower alkyl; R₁ is H, F, an alkyl group, OH, SH, oran O-alkyl group; R₂ and R₃ are each independently H;

where n is an integer from 0 to 5, A₁ is CH or N, A₂ and each A₃ areindependently selected from C(R₄₁)(R₄₁), N(R₄₁), S, S(O), S(O)₂, and O,and A₄ is NH or NR₄₁, where each R₄₁ is independently H or lower alkyl,provided that no more than 2 heteroatoms occur consecutively in the ringformed by A₁, A₂, (A₃)_(n), A₄ and C═O; and provided that at least oneof R₂ and R₃ is

R₅ and R₆ are each independently H, F, an alkyl group, a cycloalkylgroup, a heterocycloalkyl group, an aryl group, or a heteroaryl group;R₇ and R₈ are each independently H, an alkyl group, a cycloalkyl group,a heterocycloalkyl group, an aryl group, a heteroaryl group, —OR₁₇,—SR₁₇, —NR₁₇R₁₈, —NR₁₉NR₁₇R₁₈, or —NR₁₇OR₁₈, where R₁₇, R₁₈, and R₁₉ areeach independently H, an alkyl group, a cycloalkyl group, aheterocycloalkyl group, an aryl group, a heteroaryl group, or an acylgroup; R^(g) is a five-membered heterocycle having from one to threeheteroatoms selected from O, N, and S, or R₉ is

where R₂ is

and Z and Z₁ are each independently H, F, an alkyl group, a cycloalkylgroup, a heterocycloalkyl group, an aryl group, a heteroaryl group,—C(O)R₂₁, —CO₂R₂₁, —CN, —C(O)NR₂₁,R₂₂, —C(O)NR₂₁OR₂₂, —C(S)R₂₁,—C(S)NR₂₁R₂₂, —NO₂, —SOR₂₁, —SO₂R₂₁, —SO₂NR₂₁R₂₂, —SO(NR₂,)(OR₂₂),—SONR₂₁, —SO₃R₂₁, —PO(OR₂₁)₂, —PO(R₂₁)(R₂₂), —PO(NR₂₁R₂₂)(OR₂₃),PO(NR₂₁R₂₂)(NR₂₃R₂₄), —C(O)NR₂,NR₂₂R₂₃, or —C(S)NR₂,NR₂₂R₂₃, where R₂₁,R₂₂, R₂₃, and R₂₄ are each independently H, an alkyl group, a cycloalkylgroup, a heterocycloalkyl group, an aryl group, a heteroaryl group, anacyl group, or a thioacyl group, or any two of R₂₁, R₂₂, R₂₃, and R₂₄,together with the atom(s) to which they are bonded, form aheterocycloalkyl group, provided that Z and Z₁ are not both H; or Z₁ andR₁, together with the atoms to which they are bonded, form a cycloalkylor heterocycloalkyl group; or Z and Z₁, together with the atoms to whichthey are bonded, form a cycloalkyl or heterocycloalkyl group; or aprodrug, pharmaceutically active metabolite, pharmaceutically acceptablesalt, or solvate thereof.
 13. A method according to claim 1 utilizing arhinovirus inhibitor of the formula V:

wherein: Y is —N(R^(y))—, —C(R^(y))(R^(y))—, or —O—, where each R^(y) isindependently H or lower alkyl; R¹ is selected from optionallysubstituted alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, and—C(O)R¹⁶, where R¹⁶ is selected from optionally substituted alkyl,cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkoxy, cycloalkoxy,heterocycloalkoxy, aryloxy, heteroaryloxy, and amine; R² and R⁸ are eachindependently selected from H, F, and optionally substituted alkyl,cycloalkyl, heterocycloalkyl, aryl, and heteroaryl; R³ and R⁹ are eachindependently selected from H and optionally substituted alkyl,cycloalkyl, heterocycloalkyl, aryl, heteroaryl, —OR¹⁷, —SR¹⁷, —NR¹⁷R¹⁸,—NR¹⁹NR¹⁷R¹⁸, and —NR¹⁷OR¹⁸, where R¹⁷, R¹⁸, and R¹⁹ are eachindependently selected from H, alkyl, cycloalkyl, heterocycloalkyl,aryl, heteroaryl, and acyl; R⁴is a suitable organic moiety; each of R⁵,R⁶ and R⁷is independently H, F, or lower alkyl; m is 0 or 1; p is 0, 1,2, 3, 4, or 5; A₁ is CH or N; when m is 1, A₂ is selected fromC(R¹⁰)(R¹¹), N(R¹²), S, S(O), S(O)₂, and O; when p is not 0, each A₃ isindependently selected from C(R¹⁰)(R¹¹), N(R¹²), S, S(O), S(O)₂, and O;where R¹⁰, R¹¹ and R¹² are each independently H or lower alkyl; when pis not 0, A₄ is selected from N(R¹³), C(R¹⁰)(R¹¹), and O, and when p is0, A₄ is selected from N(R¹³)(R¹⁴), C(R¹⁰)(R¹¹)(R¹²), and O(R¹⁴),provided that when A₄ is O(R¹⁴), A₁ is not CH; where R¹⁰, R¹¹ and R¹²are each independently H or lower alkyl, R¹³ is H, alkyl, aryl, or acyl,and R¹⁴ is H, alkyl, or aryl; provided that A₁, (A₂)_(m), (A₃)_(p), andA₄ together do not include more than two consecutive heteroatoms; or aprodrug, pharmaceutically acceptable salt, pharmaceutically activemetabolite, or pharmaceutically acceptable solvate thereof.
 14. A methodaccording to claim 1 utilizing a rhinovirus inhibitor of the formula VI:

wherein: R^(a) is an alkylcarbonylalkyl, cycloalkylcarbonylalkyl,arylcarbonylalkyl, heteroarylcarbonylalkyl, alkylcarbonylaminoalkyl,cycloalkylcarbonylaminoalkyl, heterocycloalkylcarbonylaminoalkyl,arylcarbonylaminoalkyl, heteroarylcarbonylaminoalkyl,alkylaminocarbonylalkyl, cycloalkylaminocarbonylalkyl,heterocycloalkylaminocarbonylalkyl, arylaminocarbonylalkyl,heteroarylaminocarbonylalkyl group, where each alkyl, cycloalkyl,heterocycloalkyl, aryl and heteroaryl moiety thereof may beunsubstituted or substituted with one or more suitable substituents;R^(b) is H or an alkyl group, unsubstituted or substituted with one ormore suitable substituents; R^(d) is H, halo, hydroxyl, or an alkyl,alkoxy or alkylthio group, where the alkyl, alkoxy or alkylthio group isunsubstituted or substituted with one or more suitable substituents;R^(c) is a moiety having the formula:

R^(e) and R^(f) are each independently H or a lower alkyl group; m is 0or 1, provided that when m is 1, R^(a) is not an amino-substitutedalkylcarbonylalkyl or amino-substituted alkylcarbonylaminoalkyl group,and when m is 0, R^(a) is selected from an alkylaminocarbonylalkyl,cycloalkylaminocarbonylalkyl, heterocycloalkylaminocarbonylalkyl,arylaminocarbonylalkyl, heteroarylaminocarbonylalkyl andheteroarylcarbonylaminoalkyl group, provided that R^(a) is notsubstituted indolecarbonylaminoalkyl; p is an integer of from 0 to 5; A₁is CH or N; when p is 1, 2, 3, 4, or 5, A₂ is C(R^(g))(R^(h)), N(R^(i)),S, S(O), S(O)₂, or O, and when p is 0, A₂ is C(R^(g))(R^(h))(R^(i)),N(R^(g))(R^(i)), S(R^(g)), S(O)(R^(g)), S(O)₂(R^(g)), or O(R^(g)), whereeach R^(g), R^(h) and R^(i) is independently H or a lower alkyl group;each A₃ present is independently C(R^(g))(R^(h)), N(R^(i)), S, S(O),S(O)₂, or O, where each R^(g), R^(h) and R^(i) is independently H or alower alkyl group; when p is 1, 2, 3, 4, or 5, A₄ is N(R^(j)),C(R^(g))(R^(h)), or O, and when p is 0, A₄ is N(R^(j))(R^(k)),C(R^(g))(R^(h))(R^(i)), and O(R^(k)), where each R^(g), R^(h) and R^(i)is independently H or a lower alkyl group, each R^(j) is H, an alkyl,aryl, or acyl group, and each R^(k) is H or an alkyl or aryl group;provided that no more than two heteroatoms occur consecutively in theabove-depicted ring formed by A₁, (A₂)_(m), (A₃)_(p), A₄, and C═O, whereeach dotted line in the ring depicts a single bond when A₂ is presentand a hydrogen atom when A₂ is absent; and Z and Z¹ are eachindependently H, F, an alkyl, cycloalkyl, heterocycloalkyl, aryl orheteroaryl group, where the alkyl, cycloalkyl, heterocycloalkyl, aryl orheteroaryl group is unsubstituted or substituted with one or moresuitable substituents, —C(O)R^(l), —CO₂R^(l), —CN, —C(O)NR^(l)R^(m),—C(O)NR^(l)OR^(m), —C(S)R^(l), —C(S)OR^(l) —C(S)NR^(l)R^(m),—C(═NR^(l))R^(m), —C(═NR^(l))OR^(m), —NO₂, —SOR^(m), —SO₂R^(l),—SO₂NR^(l)R^(m), —SO₂(NR^(l))(OR^(m)), —SONR^(l), —SO₃R^(l),—PO(OR^(l))₂, —PO(OR^(l))(OR^(m)), —PO(NR^(l)R^(m))(OR^(n)),—PO(NR^(l)R^(m))(NR^(n)R^(o)), —C(O)NR^(l)NR^(m)R^(n),—C(S)NR^(l)NR^(m)R^(n), where R^(l), R^(m), R^(n) and R^(o) are eachindependently H or an alkyl, cycloalkyl, aryl, heterocycloalkyl, acyl orthioacyl group, where the alkyl, cycloalkyl, aryl, heterocycloalkyl,acyl or thioacyl group is unsubstituted or substituted with one or moresuitable substituents, or where any two of the R^(l), R^(m), R^(n) andR^(o), taken together with the atoms to which they are bonded, form aheterocycloalkyl group, which may be optionally substituted, or Z andR^(d), together with the atoms to which they are bonded, form acycloalkyl or heterocycloalkyl group, where Z and R^(d) are as definedabove except for moieties that cannot form the cycloalkyl orheterocycloalkyl group, or Z and Z¹, together with the atoms to whichthey are bonded, form a cycloalkyl or heterocycloalkyl group, where Zand Z¹ are as defined above; or a prodrug, pharmaceutically acceptablesalt, pharmaceutically active metabolite, or pharmaceutically acceptablesolvate of said compound.
 15. A method according to claim 1 utilizing arhinovirus inhibitor of the formula VIIA:

wherein: R^(a) is substituted or unsubstituted heterocycloalkyl orheterocycloalkylalkyl; R^(b) is a substituent having the formula:

wherein: R^(f) and R^(g) are independently H or lower alkyl; m is 1; pis an integer of from 1 to 5; A₁ is CH or N; A₂ is C(R^(h))(R^(i)),N(R^(j)), S, S(O), S(O)₂, or O; where each R^(h), R^(i) and R^(j) isindependently H or lower alkyl; each A₃ present is independentlyC(R^(h))(R^(i)), N(R^(j)), S, S(O), S(O)₂, or O; where each R^(h), R^(i)and R^(j) is independently H or lower alkyl; A₄ is N(R^(k)),C(R^(h))(R^(i)), or O; provided that no more than two heteroatoms occurconsecutively in the above-depicted ring formed by A₁, (A₂)_(m),(A₃)_(p), A₄, and C═O, where each dotted line in the ring depicts asingle bond; R^(c) is H, halogen or a substituted or unsubstituted loweralkyl group; R^(d) is H, halogen, hydroxyl, a substituted orunsubstituted alkyl, alkoxy or alkylthio group; R^(e) is H or asubstituted or unsubstituted alkylgroup; and Z and Z¹ are independentlyH, F, a unsubstituted or substituted alkyl group, cycloalkyl group,heterocycloalkyl group, aryl group or heteroaryl group, —C(O)R^(n),—CO₂R^(n), —CN, —C(O)NR^(n)R^(o), —C(O)NR^(n)OR^(o), —C(S)R^(n),—C(S)OR^(n), —C(S)NR^(n)R^(o), —NO₂, —SOR^(o), —SO₂R^(n),—SO₂NR^(n)R^(o), —SO₂(NR^(n))(OR^(o)), —SONR^(n), —SO₃R^(n),—PO(OR^(n))₂, —PO(OR^(n))(OR^(o)) —PO(NR^(n)R^(o))(OR^(p))—PO(NR^(n)R^(o))(NR^(p)R^(q)), —C(O)NR^(n)NR^(o)R^(p), or—C(S)NRNR^(o)R^(p), wherein R^(n), R^(o), R^(p) and R^(q) areindependently H, a substituted or unsubstituted alkyl group, cycloalkylgroup, aryl group, heterocycloalkyl group, acyl group or thioacyl group,or wherein any two of the R^(n), R^(o), R^(p) and R^(q), taken togetherwith the atoms to which they are bonded, form a heterocycloalkyl group,which may be optionally substituted, or Z and R^(d), together with theatoms to which they are bonded, form a cycloalkyl or heterocycloalkylgroup, or Z and Z¹, together with the atom to which they are bonded,form a cycloalkyl or heterocycloalkyl group; or a prodrug,pharmaceutically acceptable salt, or pharmaceutically acceptable solvatethereof.